1,4-benzodioxine and 1,4-benzodioxine derivatives and production thereof

ABSTRACT

Highly safe new diuretics, i.e., 1,4-benzodioxane and 1,4-benzodioxine derivatives having potent antihypertensive activity but no or little uricesuric activity, which can be administered to human orally, intravenously, or hypodermically at a respective daily dosage of 0.1-2 mg/kg, 0.005-0.1 mg/kg, or 0.02-0.4 mg/kg.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention provides novel compounds having diuretic withantihypertensive activities. More particularly, it relates to1,4-benzodioxane or 1,4-benzodioxine derivatives and processes for theproduction thereof.

2. Prior Art

1,4-Benzodioxane compounds have long been studied, for instance, it hasbeen disclosed in Journal of Medicinal Chemistry 8, 446 (1965) that2-guanidinomethyl-1,4-benzodioxane demonstrates antihypertensive actionand adrenergic blocking action. The present inventors synthesized1,4-benzodioxanesulfonamide derivatives having antihypertensive actionwhich have been disclosed in JPN Unexam. Pat. Pub. No. 55-124781.

SUMMARY OF THE INVENTION

This invention relates to a series of novel 1,4-benzodioxane and1,4-benzodioxine derivatives and a process for production thereof,having an excellent diuretic and antihypertensive activity but have noor little uricosuric activity, more particularly, it relates tocompounds of the formula: ##STR1## wherein R¹ is optionally protectedhydroxymethyl or carboxy; R² is hydrogen, straight or branched chainlower alkyl or lower alkenyl, C₄ -C₇ cycloalkyl, optionally substitutedpheny, phenyl(lower alkyl), hydroxy, thienyl, or furyl; and the dottedline indicates the presence or absence of a double bond and processesfor production of compounds represented by the above-shown formula (I),which is characterized by reaction of 3,4-dichloro-1,2-benzenediol ofthe formula: ##STR2## with α-epihalohydrin or the equivalent reagentthereof in the presence of a base followed by acylation in the presenceof Lewis acid; or characterized by acylation of3,4-dichloro-1,2-benzenediol in the presence of Lewis acid followed byreaction with α-epihalohydrin or the equivalent reagent thereof in thepresence of a base, and if necessary, subsequent oxidation ordehydrogenation after the oxidation.

DESCRIPTION OF THE PREFERRED EMBODIMENT Problem to be Resolved

Diuretic thiazides which show a moderate antihypertensive activity ororal administration have been used over many years as first-choice drug.However, it has been a severe defect that they are usually accompaniedby uricosuric action. As a result of so many studies for curing saiddefect, some sorts of phenoxy acetic acid derivatives such as thienylicacid, indacrinone and the like have been developed, but a very fewnumber of the drugs have been marketed. Developement of highly safedrugs are therefore desired.

The present inventors synthesized a series of novel 1,4-benzodioxane and1,4-benzodioxine derivatives and found that these novel compounds havean excellent diuretic and antihypertensive activity but have no orlittle uricosuric activity. Consequently the present inventors haveaccomplished this invention.

Means for Resolving the Problem

The starting materials shown by the formula (II), from which thecompounds of this invention can be prepared, are known compounds anddisclosed in Biochemical Journal 59, 410 (1955).

In this invention, representatives of the protecting group for theprotection of hydroxymethyl or carboxy are for example acyls derivedfrom fatty acids such as acetyl and propionyl as said group for theformer; and conventional ester forming groups as said group for thelatter, i.e., lower alkyls such as methyl, ethyl and propyl or phenyloptionally substituted by halogen.

Straight or branched chain lower alkyl is C₁ -C₄ alkyl and includesmethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, andt-butyl. Straight or branched chain lower alkenyl is C₂ -C₅ alkenyl andincludes for example vinyl, allyl, propenyl, isopropenyl, 1-, 2-, or3-butenyl, 1-pentenyl, 1-ethylvinyl, and 1-propylvinyl. C₄ -C₇cycloalkyl includes for example cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl. Optionally substituted phenyl is a monocyclic compoundwhich may be substituted by one or two substitutions, e.g., halogen,methyl, and ethyl. Phenyl(lower alkyl) is said lower alkyl substitutedby phenyl and includes for example benzyl, phenethyl, and phenylpropyl.

As illustrated by the following reaction scheme, the present compounds(Ia) and (Ib) are readily prepared by the reaction of3,4-dichloro-1,2-benzenediol with α-epihalohydrine or the equivalentsthereof and acylation or by acylation of 3,4-dichloro-1,2-benzenedioland reaction with α-epihalohydrine or the equivalents thereof, ifnecessary followed by oxidation or dehydrogenation after the oxidation.##STR3## Wherein R² and the dotted line each has the same meaning asdefined above, and R³ and R⁴ each is hydrogen or a protecting group.

Each step of the processes shown above is explained below.

ROUTE 1 Process 1

The reaction in this process is cycloaddition of the starting material(II) with α-epihalohydrin or the equivalents thereof and carried out inthe presence of a base. 2- Or 3-hydroxymethyl compound (Ia) or (Ib) canbe obtained selectively by specifying the reaction conditions, e.g.,sort of the base and the like.

Method Aa: ##STR4##

In the reaction for obtaining the compound (IIIa), the starting materialis subjected to cycloaddition with an equivalent or slight excess amountof α-epihalohydrin or the equivalents thereof in the presence of astrong base at an amount of about 1.5 to about 3 eq. preferably at about2 to about 2.3 eq. In this reaction, it should be cautious to choose andfix the sort and the amount of the base employed. If a strong base isemployed at an amount below 2 eq. or if the basicity of the base isweak, then the objective compound (IIIa) would be obtained in a loweryield. It is preferable to carry out this reaction at a fairly lowertemperature: for instance, the reaction is carried out at 0° C. or underreflux, more preferably at 20° to 30° C. and completed within severalminutes to several hours.

α-Epihalohydrin or the equivalents thereof employed in this inventioninvolve epihydrins substituted by halogen or electron-attracting group,wherein chlorine, bromine, and iodine are exemplified as the former andtosyloxy, mesyloxy, and the like are exemplified as the latter.

The strong base employed in this process includes alcoholate such aspotassium t-butoxide and sodium t-pentylate; amide such as sodium amide,potassium amide, lithium diethylamide, lithium diisopropylamide, andsodium bis-(trimethylsilyl)amide; and hydride such as sodium hydride andlithium hydride.

The solvent employed may be chosen according to the sort of the base orthe solubility of the reactant: for example, alcohols such as t-butylalcohol, ethers such as tetrahydrofuran (THF) and 1,2-dimethoxyethane,benzene-type solvents such as benzene, toluene, and xylene, and aproticpolar solvents such as dimethylsulfoxide and dimethylformamide (DMF).

Method Ab:

As an alternative process, the 2-hydroxy group of the starting material(II) may be protected by a suitable ethereal group and then subjected toaddition of α-epihalohydrin or the equivalents thereof.

In order to introduce said ethereal protecting group selectively at the2-hydroxy, it is preferable to employ such a base as listed above at anamount over eqivalent, preferably at about 1 to about 1.3 eq. If saidbase is employed over 2 eq. in this occasion, the protecting group wouldbe introduced at 1-hydroxy.

Any protecting group can be employed as long as they are stable to saidbase. Benzyl-type protecting groups such as benzyl, benzhydrile, andnitrobenzyl or methoxymethyl is preferable for this process. Thereaction may be carried out in a conventional manner for introduction ofprotecting groups, the solvent for which can also be chosen, asmentioned above, according to the sort of the base and solubility of thereactant.

Thus obtained 2-protected-3,4-dichlorophenol is, in the presence of abase, subjected to addition of α-epihalohydrin or the equivalentsthereof, then deprotected in a conventional manner by hydrogenolysiswith for example palladium/carbon, and cyclized by the treatment with analkali.

Method B: ##STR5##

There are two ways for obtaining the compound (IIIb) as mentioned insection (1), i.e., direct cycloaddition of α-epihalohydrin or theequivalents thereof to the starting material or cycloaddition afterintroduction of a protecting group.

For the way of the direct cycloaddition, the starting material isreacted with α-epihalohydrin or the equivalents thereof in the presenceof a weak base. It is preferable to employ said weak base at anequimolar or excess amount, preferably at 3 to 5 moles. Representativesof the weak bases employed are carbonates or hydrogencarbonates such aspotassium carbonate and sodium carbonate, organic bases such as pyridineand triethylamine, or the like. The solvent employed may be chosenaccording to the sort of the base or the solubility of the reactanttherein: for example, ketones or esters such as acetone and ethylacetate and hydrophilic solvents like alcohols such as methanol,ethanol, and isopropanol.

For the way of cycloaddition subsequent to introduction of a protectinggroup, the starting material (II) is protected at the 1-hydroxy by asuitable ethereal protecting group and then reacted with α-epihalohydrinor the equivalents thereof for cycloaddition. The introduction of theprotecting group may be carried out in a conventional manner asexplained in (1), but the sort and the amount of the base should becarefully selected and fixed. In order to introduce said etherealprotecting group selectively at the 1-hydroxy, the reaction should becarried out by using the strong base as exemplified in (1) at an amountof 2 moles or more, preferably at about 2 to about 2.3 moles.

Any protecting group stable to bases may be employed for this processand the protecting groups listed in (1) are the examples. Solventsexemplified in (1) may be also employed according to the sort of thebases or solubility of the reactants. After the introduction of theprotecting group, addition of α-epihalohydrin or the equivalentsthereof, depropection by hydrogenation or the like, and then cyclizationby treatment with alkali are carried out: theses reactions may becarried out accroding to the manners shown in (1).

Process 2

In this process, an acyl is introduced to the benzene nucleus of a 2- or3-hydroxymethyl compound (IIIa or IIIb) obtained in Process 1 to give acompound (Ia). This process may preferably be carried out after theprotection of hydroxy of the compound (III) by a protecting group stableto acids. If desired, the compounds (Ib) may be prepared by aconventional oxidation of the compound (IIIa) or (IIIb) as thecorresponding carboxylic acid, or by further esterification andintroduction of an acyl.

The introduction of acyls in this process may be carried out in aconventional manner, for example, by the Friedel Crafts reaction. Thisreaction is carried out in the presence of a Lewis acid such as alminiumchloride, zinc chloride, ferric chloride or titanium tetrachloride,wherein an acyl halide or acid anhydride having a group to be introducedas an acylating agent may be employed and chlorine, bromine, and iodineas halogen of acyl halide are exemplified.

Solvents may be chosen from usual solvents employed in the FriedelCrafts reaction according to the sort of acid catalysts or solubility ofthe reactants: for example, hydrocarbon-type solvent such asdichloromethane, dichloroethane and carbon tetrachloride, cyclohexane,carbon disulfide, nitromethane or the like may be employed.

The protected- or acyl-ester compounds obtained by the Friedel Craftsreaction may be, if desired, converted to the free alcohols by alkalihydrolysis.

Process 3

This process is characterized by the oxidation of a 2- or3-hydroxymethyl compound (Ia) to give the carboxylic acid or the ester(Ib) and the subsequent dehydrogenation to give the correspondingcarboxylic acid of dioxine-form or the ester (Ib).

All of usual oxidation reactions converting a primary or a secondaryalcohol into the carboxylic acid or the ketone may be employed as longas they are carried out under such conditions as to avoid side-reactionsat other functional groups. For instance, the Jones Oxidation methoddisclosed in Journal of Chemical Society 39 (1946), i.e., chromic acidoxidation with Jones' reagents in acetone is recommended.

The products after the oxidation may, if desired, be converted to1,4-benzodioxine compounds (Ib) by dehydrogenation.

Reactions with N-bromosuccinimide (NBS) are examples of saiddehydrogenation. The reaction is carried out, by refluxing underanhydrous conditions, in carbon tetrachloride using benzoyl peroxide asa reaction initiator and it is completed within a period of severalhours or several days.

ROUTE 2

In this Route, Process 1 and Process 2 follow the reverse course ofthose employed in Route 1. As shown in the foregoing reaction scheme,3,4-dichloro-1,2-benzenediol (II) is acylated by the Friedel Craftsreaction (Process 1') and then applied to cycloaddition (Process 2')with α-epihalohydrin or the equivalent reagent thereof to yield thecompounds (Ia). In this route, 6-acyl-1,4-dioxane or 6-acyl-1,4-dioxinederivatives are obtained.

Process 1'

This process may be carried out according to the Friedel Crafts reactionemployed in Process 2 of Route 1. The reaction conditions, i.e., thesolvents employed, the reagents, and the like may also be determinedaccording to the disclosure in Process 2 of Route 1.

Acyl group is introduced selectively at 5-position of the compound (II)and rarely at the 6-position. Since the acyl group is also reacted with1- and 2-hydroxy groups to form an ester, it is necessary to convert theester to the free alcohol by alkali hydrolysis for the subsequentprocess.

Process 2': Method A ##STR6##

In this process, the optionally protected 2-hydroxymethyl compounds(Ia-a) are prepared by cycloaddition of α-epihalohydrin or theequivalent reagent thereof to 5-acyl-3,4-dichloro-1,2-benzenediol (IV).

The process may be carried out according to Method A of Process 1 insaid route 1. The objective 2-hydroxymethyl compounds (Ia-a) can beobtained under the condition, i.e., the sort and amount of the baseemployed, the reaction temperature, the reaction time, and the like,fixed according to the Method A of Process 1.

α-Epihalohydrin or the equivalent reagent thereof may be subjected tocycloaddition directly or subsequently to protection of 2-hydroxy or thecompounds (IV) by a suitable protecting group.

Solvents employed may be chosen from the examples disclosed in Process 1in consideration of the solubility of the reactant.

Process 2': Method B

In this process, the optionally protected 3-hydroxymethyl compounds(Ia-b) are prepared by cycloaddition of α-epihalohydrin or theequivalent reagent thereof to the compounds (IV) obtained in Process 1'.

The objective compounds (Ia-b) can be obtained by the Method B ofProcess 1 by properly choosing the sort or amount of the base employedand conditions of the reaction temperature, the reaction time, and thelike.

α-Epihalohydrin or the equivalent reagent thereof may also be subjectedto cycloaddition directly or subsequently to protection of the 1-hydroxyof the compounds (IV) by a suitable protecting group.

The compounds (Ia) thus obtained through Route 2 may be, if desired,employed for the next 3rd process to obtain the compounds (Ib).

In this process, if R² is a lower alkenyl, the Friedel Crafts reactionusing acylating agent R² COX wherein R² is a lower alkenyl can beapplied and particularly if the functional group adjacent to carbonyl ofR² CO-- is for example an activated methylene --CH₂ --, the reactionwith an aldehyde or a ketone to give the alkenyl compound can also beapplied (see Example 12).

The present invention is explained in more detail by the followingExamples, which do not limit the scope of the present invention.

EXAMPLE 1 Process 1 (Method Aa) ##STR7##

To a solution of 9.04 g of 3,4-dichloro-1,2-benzenediol (II) in 190 mlof dry dimethylformamide (DMF) is added 4.25 g (2.1 equivalent weight)of a 60% sodium hydride oily suspension under cooling on an ice bath(internal temperature 5°-10° C.) and under flowing of nitrogen gas. Thetemperature of the mixture is raised to room temperature (20°-25° C.),then a solution of 8.30 g (1.2 equivalent) of epibromohydrin in 10 ml ofdry DMF is added to the mixture and the resultant mixture is stirred atroom temperature (20°-25° C.) for 1 hour. After termination of thereaction, the reaction mixture is poured into about 600 ml of ice-coldwater and extracted twice with ether. The ether layer is washed twicewith a saturated aqueous solution of sodium chloride, dried over sodiumsulfate and evaporated under reduced pressure to give 10.01 g of aresidue. The residue is chromatographed on a silica-gel column withdichloromethane, to give 1.60 g of an oily material (oil of sodiumhydride) as the first fraction, 1.22 g (Yield 8.3%) of2-(2,3-epoxypropyloxymethyl)-7,8-dichloro-1,4-benzodioxane as the secondfraction, and 6.17 g of 2-hydroxymethyl-7,8-dichloro-1,4-benzodioxane(IIIa) as the last fraction. Yield 52%. The last fraction isrecrystallized from hexane-ether to give a pure substance, m.p. 53°-55°C.

Process 1 (Method Ab) ##STR8##

To a solution of 8.95 g (0.05 mole) of the compound (II) dissolved in300 ml of dry DMF is added a solution of 2.2 g (0.055 mole) of 60%sodium hydride oily suspension and 9.4 g (0.055 mole) of benzyl bromidein 30 ml of DMF. The mixture is stirred at 100° C. for 2 hours, thenpoured into 400 ml of water and extracted with ether. The ether layer iswashed twice with 100 ml of a diluted aqueous solution of sodiumhydroxide, washed with water, dried and then evaporated to give 5.9 g ofa residue. This is recrystallized from hexane to give 3.79 g of1,2-dibenzyloxy-3,4-dichlorobenzene. Yield 21.1%, mp. 74°-75.5° C.

Anal. Calcd. (%) for C₂₀ H₁₆ O₂ Cl₂ (MW. 359.256): C 66.87, H 4.49, Cl19.74, Found (%): C 67.49, H 4.75, Cl 19.44.

IR(Nujol) νmax: 1585 cm⁻¹.

NMR(CDCl₃) δppm: about 7.36(10H), 7.12, 6.78(2×1H, d, 9 Hz) 5.07,5.04(2×2H, s).

The above sodium hydroxide layer is acidified with hydrochloric acid andextracted with ether. The organic layer is washed with water, dried andevaporated to give 8.37 g of a residue. This is chromatographed on 150 gof silica-gel and eluted with benzene. The eluate is recrystallized frompentane to give 5.464 g of 1-hydroxy-2-benzyloxy-3,4-dichlorobenzene.

Yield 40.6%, mp. 61° C.

Anal. Calcd. (%) for C₁₃ H₁₀ O₂ Cl₂ (MW. 269.13): C 58.02, H 3.75, Cl26.35, Found (%): C 57.32, H 3.82, Cl 26.12.

IR(Nujol) νmax: 3400, 1590, 1570 cm⁻¹.

NMR(CDCl₃) δppm: about 7.40(5H), 7.12, 6.75(2×1H, d, 9 Hz), 5.41(1H, s),5.05(2H, s).

To a solution of 2.69 g of 1-hydroxy-2-benzyloxy-3,4-dichlorobenzenedissolved in 100 ml of dry DMF are added 480 mg of 60% sodium hydrideoily suspension and 1.685 g of epibromohydrin, and the mixture isstirred at 80° C. for 6 hours. The reaction mixture is poured into 200ml of water and extracted three times with 200 ml of ether. The organiclayer are washed with water, dried and evaporated to give 3.5 g of aresidue. This is recrystallized from n-hexane to give 2.569 g of1-(2,3-epoxypropyloxy)-2-benzyloxy-3,4-dichlorobenzene, yield 79.0%, mp.65° C.

Anal. Calcd. (%) for C₁₆ H₁₄ O₃ Cl₂ (molecular weight 325.194): C 59.10,H 4.34, Cl 21.80, Found (%): C 58.87, H 4.24, Cl 22.06.

IR(Nujol) νmax: 1580 cm⁻¹.

NMR(CDCl₃) δppm: 7.59-7.23(5H), 7.13, 6.78(2×1H, d, J=9 Hz), 5.05(2H,s), 4.33-3.81(2H), about 3.32(1H), 2.90-2.64(2H).

In 140 ml of ethyl acetate, 5.595 g of1-(2,3-epoxypropyloxy)-2-benzyloxy-3,4-dichlorobenzene is hydrogenatedunder atmospheric pressure using 1.65 g of 5% palladium on carbon (50%moisture) as catalyst (for 20 minutes, 625 ml of hydrogen gas isabsorbed.). After the catalyst is filtered off, the filtrate isevaporated to give 4.3 g of1-(2,3-epoxypropyloxy)-2-hydroxy-3,4-dichlorobenzene.

NMR(CDCl₃) δppm: 6.93, 6.74(2×1H, d, J=9 Hz), 4.41-3.91(2H),3.47-3.30(1H), 3.01-2.79(2H).

To a solution of the product dissolved in 50 ml of ethanol is added 10ml of 2N sodium hydroxide, and the mixture is heated at 80° C. for 5minutes, then concentrated to give a residue, to which water is addedand extracted with ether. The organic layer is washed with water, driedand evaporated to give 3.16 g of a residue, which is passed through acolumn of 20 g of silica-gel and eluted with dichloromethane to give3.104 g of an objective compound,2-hydroxymethyl-7,8-dichloro-1,4-benzodioxane (IIIa).

Yield 76.7%, mp. 53°-55° C.

Anal. Calcd. (%) for C₉ H₈ O₃ Cl₂ (molecular weight 235.068): C 45.99, H3.43, Cl 30.16, Found (%): C 46.07, H 3.53, Cl 29.53.

IR(CHCl₃) νmax: 3580, 3400, 1590, 1570 cm⁻¹.

NMR(CDCl₃) δppm: 6.94, 6.72(2×1H, d, J=9 Hz), 4.38-4.03(3H),3.96-3.83(2H), 2.13(1H, t, J=6 Hz).

Process 2: Method Aa ##STR9##

A solution of 4 g of the compound (IIIa), 7.9 g (5 equivalent) ofpropionyl chloride, and 9.06 g (4 equivalent) of aluminium chloridedissolved in 50 ml of dry dichloromethane is stirred at room temperaturefor 30 minutes and then refluxed for 2 hours. After cooled, the reactionmixture is poured into a mixture of concentrated hydrochloric acid withice, and extracted three times with dichloromethane. The organic layeris washed with a saturated aqueous solution of sodium chloride, with 2Nsodium hydroxide, and then twice with saturated aqueous solution ofsodium chloride, dried over sodium sulfate, and evaporated under reducedpressure to give 6.00 g of a residue. Immediately, this 6.00 g isdissolved in 60 ml of dioxane and 30 ml of 1N sodium hydroxide, and thesolution is heated for 5-10 minutes (which becomes a clear solution) andallowed to stand for about an hour. The resulting solution is pouredinto about 150 ml of water, extracted three times with dichloromethane.The organic layer is washed twice with a saturated aqueous solution ofsodium chloride, dried over sodium sulfate and evaporated under reducedpressure to give 5.10 g of a crystalline residue, which isrecrystallized from ether to give 1.95 g of2-hydroxymethyl-5-propionyl-7,8-dichloro-1,4-benzodioxane (Ia-a1), mp.121°-123° C. The compound (Ia-a1) is further recrystallized fromdichloromethane-ether to give 1334 mg of a pure product (Ia-a1), yield27% [the first crop: 1114 mg (mp. 124°-125° C.) and the second crop: 220mg (mp. 122°-124° C.)]. Crystalline residue (3580 mg) is recovered fromthe mother liquor.

In 30 ml of pyridine and 20 ml of acetic anhydride is dissolved 3.58 gof the crystalline residue containing the compound (Ia-a1) and2-hydroxymethyl-6-propionyl-7,8-dichloro-1,4-benzodioxane (Ia-a2), andthe solution is allowed to stand overnight at room temperature to give2-acetoxymethyl-5-propionyl-7,8-dichloro-1,4-benzodioxane (Ia-a3) and2-acetoxymethyl-6-propionyl-7,8-dichloro-1,4-benzodioxane (Ia-a4),respectively. After the solvent is removed by evaporation under reducedpressure, the residue is extracted three times with dichloromethane. Theorganic layer is washed twice with a saturated aqueous solution ofsodium chloride, dried over sodium sulfate, and evaporated to give 4.00g of a residue. The residue is separated into two fractions by using twocolumns of Lober B (Merck) with hexane:acetone (4:1) as an eluent. Theformer fraction gives 1380 mg of the compound (Ia-a3), which isrecrystallized from ether-hexane to give 1303 mg of the pure product(Ia-a3), yield 23%, mp. 67°-70° C. The latter fraction gives 2180 mg ofthe compound (Ia-a4), which is recrystallized from ether-hexane to give2050 mg of the pure product (Ia-a4), yield 36%, mp. 74°-77° C.

A solution of 1305 mg of the compound (Ia-a3) dissolved in 20 ml ofdioxane and 10 ml of 1N sodium hydroxide is heated for 5-10 minutes,then allowed to stand at room temperature for 1 hour, poured into waterand then extracted three times with dichloromethane. The organic layeris washed twice with a saturated aqueous solution of sodium chloride,dried over sodium sulfate, and evaporated to give 1200 mg of a residue,which is recrystallized from ether-hexane to give 1000 mg of the pureproduct (Ia-a1), yield 88%, mp. 122°-124° C.

Process 2 (General Procedure for Method Aa) ##STR10##

In about 25-30 ml of dry dichloromethane or carbon disulfied aredissolved 8 mmol of a starting material (IIIa) and acylhalide:aluminumchloride (4.0:3.0 equivalent or 5.0:4.0 equivalent), and the solution isstirred at room temperature for 30 minutes and refluxed for 2 hours onan oil bath. After cooled, the reaction mixture is poured into an icedconcentrated hydrochloric acid, and extracted three times withdichloromethane. The organic layer is washed with a saturated aqueoussolution of sodium chloride, then with 2N sodium hydroxide, and twicewith a saturated aqueous solution of sodium chloride, dried overmagnesium sulfate and evaporated to give an acyl ester. Subsequently,the acyl ester is refluxed in 2N sodium hydroxide/ethanol for 10minutes, and the reaction mixture is extracted with dichloromethane togive a mixture of 5-acyl alcohol and 6-acyl alcohol (Ia-a:R₃ =H). Themixture is, if necessary, separated by acylation into 5-acyl and 6-acylcompounds (Ia-a:R₃ =acyl).

Process 2 (Method Ab) ##STR11##

A solution of 3.00 g of the compound (IIIa), 7.5 g (4 equivalent) of2-thenoyl chloride and 5.2 g (3 equivalent) of aluminium chloride in 30ml of dry dichloromethane is stirred at room temperature for 30 minutes,then warmed up to 90° C. on an oil bath. The solvent is removed and themixture is kept at the same temperature for 2.5 hours. After cooled, thereaction mixture is poured into an iced concentrated hydrochloric acid.The separated aqueous layer is extracted three times withdichloromethane, then with a saturated aqueous solution of sodiumchloride, with 2N sodium hydroxide and twice with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate and thenevaporated to give 9.50 g of a residue. A solution of 9.50 g of theresidue dissolved in 100 ml of ethanol and 50 ml of 2N sodium hydroxideis refluxed for 30 minutes, the ethanol is evaporated under reducedpressure, and the residue is extracted with dichloromethane three times.The organic layer is washed twice with water, dried over sodium sulfate,and then evaporated to give 4.250 g of a mixture of2-hydroxymethyl-5-thenoyl-7,8-dichloro-1,4-benzodioxane (Ia-a5) and2-hydroxymethyl-6-thenoyl-7,8-dichloro-1,4-benzodioxane (Ia-a6). Thismixture is separated by using two columns of Lober B (Merck) withdichloromethane:acetone (20:1) as an eluant into 1990 mg of the compound(Ia-a6) as the first half fraction and 2010 mg of the compound (Ia-a5)as the latter half. They are recrystallized from ethanol-hexane to give1860 mg (yield 42%) of the pure compound (Ia-a6), mp. 113°-114° C. and1985 mg (yield 45%) of the pure compound (Ia-a5), mp. 122°-125° C.,respectively.

Process 2 (General Procedure for Method Ab)

A solution of 8 mmol of the compound (IIIa) and acyl hydride:aluminiumchloride (4.0:3.0 equivalent) dissolved in 10-30 ml of anhydrousdichloromethane is stirred at room temperature for 30 minutes thenplaced on an oil bath and kept at 90° C., at which temperature thesolvent is removed. The mixture is kept at 90° C. (bath temperature) for2.5 hours, and then worked up in the same manner as in the generalprocedure in Process 2 (Method A) to give the compound (Ia-a).

The compounds prepared according to Method Aa and Method Ab, theirreaction conditions and physical constants are shown in Tables 4 and 5.

                                      TABLE 4                                     __________________________________________________________________________    Reaction conditions of Method Aa and Method Ab                                (A): Method Aa (B): Method Ab                                                 R.sub.2 of alkylating     Compd. No. Compd. No.                               agent   R.sub.2 COCl:AlCl.sub.3                                                               Reaction conditions                                                                     5-Acyl I a-a, (yield %)                                                                  6-Acyl I a-a, (yield                     __________________________________________________________________________                                         %)                                       m-chlorophenyl                                                                        4.0:3.0 (B)       23 (21.0)  24 (30.6)                                p-chlorophenyl                                                                        4.0:3.0 (B)       25 (46.6)  26 (42.2)                                o-fluorophenyl                                                                        4.0:3.0 (B)       27 (49.4)  28 (33.2)                                o-tolyl 4.0:3.0 (B)       29 (38.0)  30 (43.8)                                m-tolyl 4.0:3.0 (B)       31 (40.9)  3.2 (38.9)                               p-tolyl 4.0:3.0 (B)       33 (23.1)  34 (27.8)                                2-thienyl                                                                             4.0:3.0 (B)        5 (45)     6 (42)                                  2-furyl 4.0:3.0 (B)       35 (47)    36 (48)                                  benzyl  3.0:3.0 CS.sub.2, r.t., 12 hrs.                                                                 37 (17.4)  38 (6.3)                                 __________________________________________________________________________     r.t.: room temperature                                                   

                                      TABLE 5                                     __________________________________________________________________________                          Elementary anal.                                        compd.                                                                            Position     m.p. C; Calcd. (%),                                                                              IR(cm.sup.-1)                             I a-a                                                                             acylated                                                                           R.sub.2                                                                             R.sub.3                                                                         °C.                                                                         F; Found (%)  NMR(δ, Hz)                          __________________________________________________________________________    1   5    Et    H 126˜128                                                                      C.sub.12 H.sub.12 O.sub.4 Cl.sub.2 (Mw 291,                                                 IRνmax(Nujol) 3480,1675,1585                                 C H Cl        NMR(d.sub.6 -acetone)                                                         7.34(1H,s),4.65-4.23(3H,m),                                     C; 49.51 4.15 24.36                                                                         3.96˜3.85(2H,m),2.98(2H,q,J =                                           8),2.77(1H,s),1.08                                              F; 49.36 4.17 24.58                                                                         (3H,t,J = 8)                              2   6    Et    H  96˜100                                                                      C.sub.12 H.sub.12 O.sub.4 Cl.sub.2 (Mw 291,                                                 IRνmax(Nujol) 3520,1685,1595,1559                            C H Cl        NMR(d.sub.6 -acetone)                                                         7.07(1H,s),4.70˜3,50(6H,m),                               C; 49.51 4.15 24.36                                                                         2.90(2H,q,J = 7.01),1.12(3H,t,J =                                             7.0)                                                            F; 49.50 4.30 24.43                                     3   5    Et    Ac                                                                              75˜76                                                                        C.sub.14 H.sub.14 O.sub.5 Cl.sub.2 (Mw 333,                                                 IRνmax(Nujol) 1730,1675,1580                                 C H Cl        NMR(d.sub.6 -acetone) 7.34(1H,s),                                             4.73˜4.17(5H,m),                                          C; 50.47 4.24 21.28                                                                         2.96(2H,q,J = 8),2.03(3H,s),1.09(3H,t,                                        J = 8)                                                          F; 50.29 4.25 21.56                                     4   6    Et    Ac                                                                              70˜73                                                                        C.sub.14 H.sub.14 O.sub.5 Cl.sub.2 (Mw 333,                                                 IRνmax(Nujol) 1742,1688,1595,1558                            C H Cl        NMR(CDCl.sub.3) 7.00(1H,s),4.67˜                                        3.90(5H,m),2.90(2H,                                             C; 50.47 4.23 21.28                                                                         q,J = 7),2.10(3H,s),1.17(3H,t,J = 7)                            F; 50.29 4.23 21.21                                     5   5    2-thienyl                                                                           H 136˜137                                                                      C.sub.14 H.sub.10 O.sub.4 Cl.sub.2 S(Mw 345,                                                IRνmax(Nujol) 3480˜3430(br),1                                        630,1582                                                        C H Cl S      NMR(CDCl.sub.3) 7.75(1H,dd,J =                                                1.5,5.5),7.52(1H,dd,J =                                         C; 48.71 2.92 20.54 9.29                                                                    1.5,4.5),7.13(1H,dd,J                                                         = 5.5,4.5),7.14(1H,s),                                          F; 48.79 3.04 20.37 9.11                                                                    4.91˜4.06(3H,m),3.92(2H,d,J =                                           6),2.75(1H,t,J = 7)                       6   6    2-thienyl                                                                           H 113˜114                                                                      C.sub.14 H.sub.10 O.sub.4 Cl.sub.2 S(Mw                                                     NMR(CDCl.sub.3) 7.73(1H,dd,J =                                                5.1),7.45(1H,dd,J =                                             C H Cl S      5.1),7.17(1H,t,J = 5),6.97(1H,s),3.72.                                        about. 4.28(1H,                                                 C; 48.71 2.92 20.54 9.29                                                                    m),4.30(2H,ABq),3.95(2H,q),2.13(1H,t,J                                         = 7)                                                           F; 48.62 3.16 20.54 9.31                                7   5    Me    H 101˜102                                                                      C.sub.11 H.sub.10 O.sub.4 Cl.sub.2 (Mw 277,                                                 IRνmax(Nujol) 3500,1683,1580,1550                            C H Cl        NMR(CDCl.sub.3) 7.45(1H,s),4.56˜                                        4.18(3H,m),ca.3.96                                              C; 47.68 3.64 25.59                                                                         (2H),2.57(3H,s),2.47(1H,t,J = 7)                                F; 47.53 3.64 25.45                                     8   5    Me    Ac                                                                              69˜71                                                                        C.sub.13 H.sub.12 O.sub.6 Cl.sub.2 (Mw 319,                                                 IRνmax(Nujol) 1750,1685,1662,1582                            C H Cl        NMR(CDCl.sub.3) 7.44(1H,s),4.59˜                                        4.02(5H,m),2.56(3H,                                             C; 48.93 3.79 22.22                                                                         s),2.11(3H,m)                                                   F; 48.69 3.82 22.11                                     9   6    Me    H 72˜73                                                                        C.sub.11 H.sub.10 O.sub.4 Cl.sub.2 (Mw 277,                                                 IRνmax(Nujol) 3560,1680,1598,1550                            C H Cl        NMR(CDCl.sub.3) 7.10(1H,s),4.45˜                                        4.10(3H,m),ca.3.94                                              C; 47.68 3.64 25.59                                                                         (2H),2.60(1H,s),2.39(1H,t,J = 7)                                F; 47.44 3.70 25.55                                     10  6    Me    Ac                                                                              95˜96                                                                        C.sub.13 H.sub.12 O.sub.5 Cl.sub. 2 (Mw 319,                                                IRνmax(Nujol) 1740,1680,1590,1560                            C H Cl        NMR(CDCl.sub.3) 7.07(1H,s),4.63˜                                        3.95(5H,m),2.58(3H,                                             C; 48.93 3.79 22.22                                                                         s),2.10(3H,m)                                                   F; 48.82 3.74 22.17                                     11  5    propyl                                                                              H 116˜118                                                                      C.sub.13 H.sub.14 O.sub.4 Cl.sub.2 (Mw 305,                                                 IRνmax(Nujol) 3470,1655,1575                                 C H Cl        NMR(CDCl.sub.3) 7.39(1H,s),4.53˜                                        4.16(3H,m),4.01˜                                          C; 51.17 4.62 23.23                                                                         3.88(2H,m),2.90(2H,t,J                                                        = 7),2.36(1H,t,J = 6),1.88˜                               F; 51.11 4.71 23.01                                                                         1.47(2H,m),0.94(3H,t,J = 7)               12  6    propyl                                                                              H 66˜68                                                                        C.sub.13 H.sub.14 O.sub.4 Cl.sub.2 (Mw 305,                                                 IRνmax(Nujol) 3440,1690,1595                                 C H Cl        NMR(CDCl.sub.3) 6.96(1H,s),4.44˜                                        4.08(3H,m),ca.3.93                                              C; 51.17 4.62 23.24                                                                         (2H),2.86(2H,t,J = 7),2.30(1H,t,J =                                           6),1.75(2H,m),                                                  F; 51.03 4.54 23.11                                                                         0.95(3H,t,J = 8)                          13  5    isopropyl                                                                           H oil  C.sub.13 H.sub.14 O.sub.4 Cl.sub.2 (Mw 305,                                                 IRνmax(CHCl.sub.2)                                                         3600,3400(br),1685,1580                                                       NMR(d.sub.6 -acetone)                                                         7.23(1H,s),4.63˜4.13(3H),ca.                                            3.90(2H),2.75(1H,s),3.47(1H,m),1.08(6H                                        ,d,J = 6)                                 14  5    n-butyl                                                                             H 80˜81                                                                        C.sub.14 H.sub.16 O.sub.4 Cl.sub.2 (Mw 319,                                                 IRνmax(Nujol) 3500,1663,1578                                 C H Cl        NMR(CDCl.sub.3) 7.40(1H,s),4.53˜                                        4.15(3H),ca.3.95                                                C; 52.68 5.05 22.22                                                                         (2H),2.92(2H,t,J = 7),2.30(1H,t,J =                                           6),1.79˜1.15(2 ×                                    F; 52.53 4.85 22.37                                                                         2H),0.90(3H,t,J = 7)                      15  6    n-butyl                                                                             H oil  C.sub.14 H.sub.16 O.sub.4 Cl.sub.2 (Mw 319,                                                 IRνmax(CHCl.sub.3)                                                         3580,3400,1693,1600                                                           NMR(CDCl.sub.3) 6.97(1H,s),4.46˜                                        4.11(3H),ca.3.94                                                              (2H),2.90(2H,t,J = 7),2.30(1H,t,J =                                           6),1.74˜1.25(2                                                          × 2H),0.93(3H,t,J = 7)              16  5    cyclopentyl                                                                         H oil  C.sub.16 H.sub.16 O.sub.4 Cl.sub.2 (Mw 331,                                                 IRνmax(CHCl.sub.3)                                                         3590,3400,1700,1582                                                           NMR(d.sub.6 -acetone)                                                         7.24(1H,s),4.63˜4.14(3H),ca.                                            3.88(2H),3.70(1H,m),2.89(1H,s),1.86.ab                                        out.1.59(8H)                              17  6    cyclohexyl                                                                          H oil                IRνmax(CHCl.sub.3)                                                         3570,3370(br),1690,1600                                                       NMR(d.sub.6 -acetone)                                                         6.82(1H,s),4.42˜4.06(3H),ca.                                            3.92(2H),ca.3.0,ca.2.18(2 ×                                             1H),1.95˜1.24(1OH)                  18  5    benzyl                                                                              H 148˜151                                                                      C.sub.17 H.sub.14 O.sub.4 Cl.sub.2 (Mw 353,                                                 IRνmax(Nujol) 3480,1670,1575                                 C H Cl        NMR(d.sub.6 -acetone)                                                         7.27(1H,s),7.22(5H,s),4.66˜                               C; 57.81 4.00 20.07                                                                         4.14(3H),4.26(2H,s),ca.3.87(2H),2.72(1                                        H,s)                                                            F; 57.98 4.08 19.83                                     19  5    phenyl                                                                              H 158˜159                                                                      C.sub.16 H.sub.12 O.sub.4 Cl.sub.2 (Mw 339,                                                 IRνmax(Nujol) 3430,1643,1590,1572                            C H Cl        NMR(CDCl.sub.3) 7.83˜7.23(5H),7.                                        07(1H,s),4.44˜4.03                                        C; 56.66 3.57 20.91                                                                         (3H),ca.3.89(2H),2.25(1H,t,J = 7)                               F; 56.55 3.76 20.98                                     20  6    phenyl                                                                              H oil                IRνmax(CHCl.sub.3)                                                         3590,3400,1665,1595                                                           NMR(CDCl.sub.3) 7.86˜7.09(5H),6.                                        89(1H,s),4.46˜4.13                                                      (3H),4.03˜3.90(2H),2.32(1H,t,J                                          = 7)                                      21  5    o-chloro-                                                                           H oil                IRνmax(CHCl.sub.3)                                                         3600,3450˜3350,1675                          phenyl                     NMR(CDCl.sub.3) ca.7.36(4H),7.29(1H,s)                                        ,4.37˜3.97                                                              (3H),ca.3.85(2H),2.22(1H,t,J = 6)         22  6    o-chloro-                                                                           H oil                IRνmax(CHCl.sub.3)                                                         3600,3450˜3400(br),1682                      phenyl                     NMR(CDCl.sub.3) ca.7.38(4H),7.00(1H,s)                                        ,4.42˜ 407                                                              (3H),ca.3,92(2H),2.29(1H,br)              23  5    m-chloro-                                                                           H 96˜98                                                                        C.sub.16 H.sub.11 O.sub.4 Cl.sub.3 (Mw 373,                                                 IRνmax(CHCl.sub.3)                                                         3560,3400˜3350(br),1660                      phenyl       C H Cl        NMR(CDCl.sub.3) 7.73˜7.22(4H),7.                                        07(1H,s)4.36˜4.03                                         C; 51.44 2.97 28.47                                                                         (3H),ca.3.89(2H),2.17(1H,t,J = 6)                               F; 51.13 3.10 28.45                                     24  6    m-chloro-                                                                           H 144˜146                                                                      C.sub.16 H.sub.11 O.sub.4 Cl.sub.3 (Mw 373,                                                 IRνmax(Nujol) 3530,1655                         phenyl       C H Cl        NMR(CDCl.sub.3) 7.75˜7.24(4H),6.                                        87(1H,s),4.45˜4.11                                        C; 51.44 2.97 28.47                                                                         (3H),ca.3.94(2H),2.22(1H,t,J = 6)                               F; 51.54 3.05 28.34                                     25  5    p-chloro-                                                                           H oil                IRνmax(CHCl.sub.3)                                                         3590,3400˜3350(br),1670                      phenyl                     NMR(d.sub.6 -acetone) 7.85,7.52(2                                             × 2H,d,J = 9),7.12                                                      (1H,s),4.50˜3.97(3H),ca.3.85(2H)                                        ,2.74(1H,s)                               26  6    p-chloro-                                                                           H oil                IRνmax(CHCl.sub.3)                                                         3590,3400˜3350(br,1673                       phenyl       NMR(d.sub.3 -acetone) 7.78,7.53(2 × 2H,d,J =                            9),6.96                                                                                     (1H,s),4.56˜4.07(3H),ca.3.90(2H)                                        ,2.75(1H,s)                               27  5    o-fluoro-                                                                           H oil  C.sub. 16 H.sub.11 O.sub.4 Cl.sub.2 F(Mw 357,                                               IRνmax(CHCl.sub.3)                                                         3590,3380,1685,1610                                phenyl                     NMR(CDCl.sub.3) 7.77˜6.94(4H),7.                                        23(1H,s),4.42˜4.00                                                      (3H),3.87(2H,t,J = 7),2.33(1H,t,J =                                           7)                                        28  6    o-fluoro-                                                                           H 109˜110                                                                      C.sub.16 H.sub.11 O.sub.4 Cl.sub.2 F(Mw 357,                                                IRνmax(Nujol) 3420,1665,1610                    phenyl       C H Cl F      NMR(CDCl.sub.3) 7.80˜7.08(4H,m),                                        6.99(1H,s),4.46˜                                          C; 53.81 3.10 19.85 5.32                                                                    4.11(1H,m),ca.4.33(2H),ca.3.95(2H),2.2                                        0(1H,t,J =                                                      F; 53.87 3.18 19.86 5.10                                                                    6)                                        29  5    o-tolyl                                                                             H oil                IRνmax(CHCl.sub.3)                                                         3410˜3350(br),1660                                                      NMR(CDCl.sub.3) 7.49˜7.18(4H),7.                                        11(1H,s),4.43˜4.02                                                      (3H),ca.3.89(2H),2.6˜2.3(br,1H),                                        2.46(3H,s)                                30  6    o-tolyl                                                                             H oil                IRνmax(CHCl.sub.3)                                                         3570,3400˜3350,1662                                                     NMR(CDCl.sub.3) 7.47˜7.06(4H),6.                                        91(1H,s),4.42˜4.07                                                      (3H),ca.3.91(2H),2.51(3H,s),2.39(1H,t,                                        J = 6)                                    31  5    m-tolyl                                                                             H oil                IRνmax(CHCl.sub.3)                                                         3570,3420˜3350,1662                                                     NMR(CDCl.sub.3) 7.61˜7.23(4H),7.                                        05(1H,s),4.39˜3.98                                                      (3H),ca.3.90(2H),2.39(3H,s),ca.2.31(1H                                        )                                         32  6    m-tolyl                                                                             H oil                IRνmax(CHCl.sub.3)                                                         3580,3420˜3350,1665                                                     NMR(CDCl.sub.3) 7.62˜7.23(4H),6.                                        86(1H,s),4.44˜4.09                                                      (3H),ca.3.95(2H),2.38(3H,s),ca.2.24(1H                                        )                                         33  5    p-tolyl                                                                             H oil                IRνmax(CHCl.sub.3)                                                         3580,3410˜3360,1660                                                     NMR(CDCl.sub.3) 7.68,7.22(2 ×                                           2H,d,J = 8),7.03(1H,s),                                                       4.39˜3.99(3H),ca.3.89(2H),2.40(3                                        H,s),2.30(1H,                                                                 t,J = 6)                                  34  6    p-tolyl                                                                             H oil                IRνmax(CHCl.sub.3)                                                         3580,3410˜3360,1662                                                     NMR(CDCl.sub.3) 7.68,7.22(2 ×                                           2H,d,J = 8),6.85(1H,s),                                                       4.43˜4.08(3H),ca.3.93(2H),2.40(3                                        H,s),2.25(1H,                                                                 t,J = 6)                                  35  5    2-furyl                                                                             H 143˜145                                                                      C.sub.14 H.sub.10 O.sub.6 Cl.sub.2 (Mw 329,                                                 IRνmax(Nujol) 3280,1642,1588,1560                            C H Cl        NMR(CDCl.sub.3) 7.67(1H,dd,J =                                                0.5,2.0),7.17(1H,s),                                            C; 51.09 3.06 21.54                                                                         7.13(1H,dd,J = 0.5,4.0),6.56(1H,dd,J                                          = 2.0,4.0),                                                     F; 51.25 3.19 21.78                                                                         4.42˜4.06(3H),3.93(2H,t,J =                                             5),2.43(1H,t,j = 6)                       36  6    2-furyl                                                                             H 112˜114                                                                      C.sub.14 H.sub.10 O.sub.5 Cl.sub.2 (Mw 329,                                                 IRνmax(Nujol) 3320˜3270,3100,                                        1648,1598                                                       C H Cl        NMR(CDCl.sub.3) 7.64(1H,dd,J =                                                0.5,2.0),7.07(1H,dd,J =                                         C; 51.09 3.06 21.54                                                                         0.5,4.0),6.95(1H,s),6.50(1H,dd,J =                                            2.0,4.0),                                                       F; 51.24 3.13 21.51                                                                         4.43˜4.08(3H),ca.3.93(2H),2.33(1                                        H,t,J = 6)                                37  5    benzyl                                                                              H 148˜151                                                                      C.sub.17 H.sub.14 O.sub.4 Cl.sub.2 (Mw 353,                                                 IRνmax(Nujol) 3480,1670,1575                                 C H Cl        NMR(d.sub.6 -acetone)                                                         7.27(1H,s),7.22(5H,s),4.66˜                               C; 57.81 4.00 20.07                                                                         4.14(3H,m),4.26(2H,s),4.00˜3.75(                                        2H,m),2.72(1H,                                                  F; 57.98 4.08 19.83                                                                         s)                                        38  6    benzyl                                                                              H 117˜122                                                                      C.sub.17 H.sub.14 O.sub.4 Cl.sub.2                                                          IRνmax(Nujol) 3520,1686,1606,1592                            C H Cl        NMR(CDCl.sub.3) 7.23(5H,s),6.90(1H,s),                                        4.47˜4.00(3H,                                             C; 57.81 4.00 20.07                                                                         m),4.17(2H,s),4.00˜3.73(2H,m),2.                                        27˜1.86(1H,m)                                             F; 57.79 3.97 20.09                                     __________________________________________________________________________

EXAMPLE 2 Process 1 (Method Ba) ##STR12##

A solution of 5 g of the compound (II), 15.5 g (4 equivalent) ofpotassium carbonate and 5.75 g (1.5 equivalent) of epibromohydrin in 150ml of acetone is refluxed for about 10 hours under stirring. Afterconfirmation of disappearance of the starting material spot by thinlayer chromatography (TLC, dichloromethane:acetone=20:1), the reactionmixture is filtered in order to remove insoluble material, which iswashed well with acetone. The filtrate is evaporated under reducedpressure to give a residue, which is extracted three time withdichloromethane. The organic layer is washed with 2N sodium hydroxide,washed twice with water, dried over sodium sulfate and evaporated togive 6.95 g of a residue, which is chromatographed on 10 g of silica-gelfor decolorization and eluted with benzene and with dichloromethane togive 6.30 g of the objective3-hydroxymethyl-7,8-dichloro-1,4-benzodioxane (IIIb). The physicalconstants of the compound (IIIb) are shown in Process 1 (Method Bb).

Process 1 (Method Bb) ##STR13##

In 250 ml of dimethylformamide is dissolved 8.95 g of the compound (II),and 4.80 g (2 equivalent) of 50% sodium hydride oily suspension and10.25 g (1.3 equivalent) of benzyl bromide are added thereto. Themixture is stirred for 10 minutes under ice cooling, then poured into200 ml of water, and sparingly soluble crystals are collected byfiltration and recrystallized from hexane to give 2.096 g of1,2-dibenzyloxy-2-hydroxy-3,4-dichlorobenzene, mp. 74°-75° C.

The filtrate is acidified with hydrochloric acid and extracted twicewith 300 ml of ether. The organic layer is washed with water, dried andevaporated to give 10.40 g of a residue, which is chromatographed on acolumn of 30 g of silica-gel and eluted with dichloromethane to give8.637 g of 1-benzyloxy-2-hydroxy-3,4-dichlorobenzene as an oil. Yield64.2%, bp. 155°-160° C.

IR(CHCl₃) νmax: 3250, 1600, 1580 cm⁻¹.

NMR(CDCl₃) δ: about 7.40(5H), 6.92, 6.73(2×1H,d,J=9 Hz), 6.00(1H,s),5.09(2H,s).

In 180 ml of dry DMF is dissolved 9.73 g of1-benzoyloxy-2-hydroxy-3,4-dichlorobenzene, and 1.91 g (1.1 equivalent)of 50% sodium hydride oily suspension and 5.45 g (1.1 equivalent) ofepibromohydrin are added thereto. The mixture is stirred at 80° C. for 4hours, then poured into 300 ml of water, and extracted twice with ether.The organic layer is washed with water, dried, and evaporated to give11.5 g of a residue, which is passed through a column of 40 g ofsilica-gel to give 10.85 g of a product as a dichloromethane fraction.This is recrystallized from n-hexane to give 9.64 g of1-benzyloxy-2-(2,3-epoxypropyloxy)-3,4-dichlorobenzene. Yield 82.0%, mp.59°-61° C.

Anal. Calcd. (%) for C₁₆ H₁₄ O₃ Cl₂ (MW. 325.194): C 59.10, H 4.34, Cl21.80, Found (%): C 59.06, H 4.27, Cl 21.86.

IR(Nujol) νmax: 1580 cm⁻¹.

NMR(CDCl₃) δppm: about 7.36(5H), 7.08, 6.78(2×1H, d, J=9 Hz), 5.05(2H,s), 4.28-3.93(2H), 3.41-3.23(1H), 2.81-2.53(2H).

In 50 ml of ethyl acetate, 1626 mg of1-benzyloxy-2-(2,3-epoxypropyloxy)-3,4-dichlorobenzene is catalyticallyhydrogenated with 500 mg of 5% palladium on carbon (50% moisture) underatmospheric pressure (for 2 hours, 153 ml of hydrogen gas absorbed).After removal of the catalyst by filtration, the solvent is evaporatedto give 1151 mg of 1-hydroxy-2-(2,3-epoxypropyloxy)-3,4-dichlorobenzene.Yield 98%. The pure product is prepared by recrystallization fromcyclohexane. mp. 92°-94° C.

Anal. Calcd. (%) for C₉ H₈ O₃ Cl₂ (MW. 235.068): C 45.99, H 3.43, Cl30.16, Found (%): C 45.36, H 3.54, Cl 29.78.

IR(Nujol) νmax: 3270-3210 (br.), 1590 cm⁻¹.

NMR(CDCl₃) δppm: 7.12, 6.78(2×1H, d, J=9 Hz), 7.9-6.3(1H, br),4.62-3.98(2H), 3.43-3.30(1H), 3.36-2.96(2H).

To a solution of 1.128 g of1-hydroxy-2-(2,3-epoxypropyloxy)-3,4-dichlorobenzene dissolved in 10 mlof ethanol is added 4 ml of 2N sodium hydroxide. The mixture is heatedat 80° C. for 5 minutes, to which water is then added and extracted withether. The organic layer is washed with water, then dried and evaporatedto give 1.120 g of the objective3-hydroxymethyl-7,8-dichloro-1,4-benzodioxane (IIb) as an oil. Yield99%.

IR(CHCl₃) νmax: 3590, 3380, 1580 cm⁻¹.

NMR(CDCl₃) δppm: 6.96, 6.75(2×1H, d, J=9 Hz), 4.72-4.01 (2×1H),3.93-3.80(2H), 2.04(1H, t, J=7 Hz).

Process 2 ##STR14##

Compounds of the general formula Ia-b are prepared according to the samemanner as in Process 2 (Method Aa and Ab), Example 1. The reactionconditions and the physical constants of the products are shown in Table6 and Table 7.

                  TABLE 6                                                         ______________________________________                                        Reaction conditions of Method I a-b.                                          (A): Method Aa (B): Method B                                                                     Reac-                                                      R.sub.2 of al-     tion    Compd. No.                                                                             Compd. No.                                kylating           condi-  5-Acyl Ia-b,                                                                           6-Acyl Ia-b,                              agent  R.sub.2 COCl:AlCl.sub.3                                                                   tions   (yield %)                                                                              (yield %)                                 ______________________________________                                        Et     6.0:5.0     (A)     1 (26.8) 2 (60.0)                                  n-propyl                                                                             3.0:2.5     (B)     --       5 (64.5)                                  2-thenoyl                                                                            4.0:3.0     (B)     6 (16.8) 7 (44.1)                                  ______________________________________                                    

                                      TABLE 7                                     __________________________________________________________________________    compd.                                                                            Position     m.p. Elementary anal.                                                                             IR(cm.sup.-1)                            Ia-b                                                                              acylated                                                                           R.sub.2                                                                            R.sub.3                                                                          °C.                                                                         C; Calcd. (%), F; Found (%)                                                                  NMR(δ,Hz)                          __________________________________________________________________________    1   5    Et   Ac 88˜89                                                                        C.sub.14 H.sub.14 O.sub.6 Cl.sub.2 (Mw 333,                                                  IRνmax(Nujol) 1730,1670,1582                                C H Cl         NMR(CDCl.sub.3) 7.40(1H,s),4.52.about                                         .3.63(5H,m),2.92(2H,                                           C; 50.47 4.24 21.28                                                                          q,J = 7),2.08(3H,s),1.15(3H,t,J =                                             7)                                                             F; 50.34 4.23 21.42                                     2   6    Et   Ac oil                 NMR(CDCl.sub.3) 7.00(1H,s),4.60.about                                         .4.07(5H,m),2.90(2H,                                                          q,J = 7),2.10(3H,s),1.20(3H,t,J =                                             7)                                       3   5    Et   H  112˜114                                                                      C.sub.12 H.sub.12 O.sub.4 Cl.sub.2 (Mw 291,                                                  IRνmax(Nujol) 3510,1668,1576                                C H Cl         NMR(CDCl.sub.3) 7.40(1H,s),4.60.about                                         .4.17(3H,m),4.05˜                                        C; 49.51 4.30 24.53                                                                          3.80(2H,m),2.63˜2.47(1H,t,J =                                           7),2.93(2H,q,J = 7),                                           F; 49.25 4.14 24.46                                                                          1.15(3H,t,J = 7)                         4   6    Et   H  84˜86                                                                        C.sub.12 H.sub. 12 O.sub.4 Cl.sub.2 (Mw 291,                                                 IRνmax(Nujol) 3300,1688,1598,1555                           C H Cl         NMR(CDCl.sub.3) 7.00(1H,s),4.55.about                                         .4.07(3H,m),3.67˜                                        C; 49.51 4.30 24.36                                                                          3.57(2H,b),2.87(2H,q,J                                                        = 7),2.00(1H,t,J = 7),1.17                                     F; 49.20 4.21 24.45                                                                          (3H,t,J = 7)                             5   6    propyl                                                                             H  oil                 IRνmax(CHCl.sub.3)                                                         3600,3430˜3370(br),1690                                                 NMR(CDCl.sub.3) 6.98(1H,s),4.53.about                                         .4.09(3H,m),3.94˜                                                       3.83(2H,m),2.86(2H,t,J                                                        = 7),2.20(1H,t,J = 7),1.90˜                                             1.50(2H,m),0.95(3H,t,J = 7)              6   5    2-thienyl                                                                          H  oil                 IRνmax(CHCl.sub.3)                                                         3450˜3400(br),1638                                                      NMR(d.sub.3 -acetone) 7.95(1H,dd,,J                                           = 1.5,5.5),7.64                                                               (1H,dd,J = 1.5,4.5),7.17(1H,dd,J =                                            5.5,4.5),7.13                                                                 (1H,s),4.67˜4.16(3H),4.68(2H,d,                                         J = 4)                                   7   6    2-thieyl                                                                           H  137˜139                                                                      C.sub.14 H.sub.10 O.sub.4 Cl.sub.2 S(Mw                                                      NMR(CDCl.sub.3) 7.73(1H,dd,J =                                                5.1),7.45(1H,dd,J =                                            C H Cl S       5.1)7.10(1H,t,J = 5),6.95(1H,s),4.13.                                         about.4.58(3H,                                                 C; 48.71 2.92 20.54 9.29                                                                     br),3.77˜4.00(2H,br),2.20(1H,t,                                         J = 7)                                                         F; 48.89 3.02 20.35 9.20                                __________________________________________________________________________

EXAMPLE 3 ##STR15##

To a solution of 2.5 g of the compound (Ia-a1) dissolved in 120 ml ofacetone is dropwise added 8N chromic acid/sulfuric acid in smallportions over a 1.5 hour period. The mixture is allowed to standovernight at room temperature. The excess amount of the chromic acid iskilled by adding methanol, the resulting precipitate is filtered off andwashed with acetone, and the filtrate is evaporated under reducedpressure to give crystals. Water is added thereto, and the crystals arecollected by filtration. The crystals (2.500 g of crystals; mp.228°-230° C.) are recrystallized from dichloromethane-ether to give2.422 g of the objective5-propionyl-7,8-dichloro-1,4-benzodioxane-2-carboic acid (Ib'-1), mp.229°-231° C. yield 92%.

General Procedure ##STR16##

To a solution of 2 g of a compound (Ia) (R₃ =H) dissolved in 100 ml ofacetone is dropwise added about 8 ml of 8N chromic acid/sulfuric acid(The reaction solution shows red color immediately after addition; thereagent is added when the red turns green) over a 2 hour period, and themixture is allowed to stand at room temperature overnight. Excess amountof the chromic acid is killed by addition of methanol, and theprecipitate is removed by filtration. The filtrate is evaporated underreduced pressure to give crystals, which are collected by eitherfiltration, or extraction with ethyl acetate or dichloromethane andrecrystallized from an appropriate solvent to give a compound (Ib') (R₄=H). Further, to a solution of 1.00 g of the compound (Ib') (R₄ =H)dissolved in 50-70 ml of dry alkanol is added, 0.3-0.5 ml ofconcentrated sulfuric acid, and the mixture is refluxed for about 3-5hours and evaporated under reduced pressure. The residue is extractedthree time with dichloromethane and the organic layer is, washed twicewith a saturated aqueous solution of sodium chloride, dried over sodiumsulfate and then evaporated to give a residue, which is recrystallizedfrom an appropriate solvent to give a compound (Ib') (R₄ =alkyl).Compounds (Ib') prepared in the same procedure as above and theirphysical constants are shown in Table 8.

    TABLE 8       Position Position      Compd. of of   mp. Elementary Anal. IR(cm.sup.-1     ) I a-b' --COR.sub.2 --COOR.sub.4 R.sub.2 R.sub.4 °C. C; Calcd.     (%), F; Found (%) NMR(δ, Hz)       1 5 2 Et H 231˜233 C.sub.12 H.sub.10 O.sub.5 Cl.sub.2 (Mw 305,     117) IRνmax(Nujol) 3170˜3150, 1763, 1670, 1580  C H Cl     NMR(d.sub.6 -acetone) 7.34(1H,s), 7.0˜5.5(1H,b), 5.28 C; 47.24     3.30 23.24  (1H, t, J = 3), 4.76, 4.48( 1H, dd, J = 13.3), 2.92(2H, F;     47.28 3.48 23.11  q, J = 8), 1.07(3H, t, J = 8) 2 5 2 Me H 206˜208 C     .sub.11 H.sub.6 O.sub.5 Cl.sub.2      (Mw 291,09) IRνmax(Nujol) 3400˜2200(b), 1740, 1683, 1583  C H     Cl  NMR(d.sub.6 -acetone) 7.38(1H,s), 7.1˜6.4(1H,b), 5.33 C; 45.39     2.77 24.36  (1H, t, J = 3), 4.81, 4.55( 1H, dd, J = 13.3), 2.53(3H,s) F;     45.14 2.98 24.56 3 5 2 n-propyl H 177˜178 C.sub.13 H.sub.12     O.sub.5 Cl.sub.2 (Mw 319, 144) IRνmax(Nujol) 3300˜2500(b),     1770, 1655  C H Cl  NMR(d.sub.6      -acetone) 8.6˜7.5(1H,b), 7.36(1H,s), 5.52 C; 48.93 3.79 22.22     (1H, t, J = 3), 4.80, 4.53( 1H, dd, J = 3.13), 2.92(2H, F; 49.13 3.89     22.17  t, J = 7), 1.64(2H,m), 0.91(3H, J =      7) 4 5 2 isopropyl H 150˜152 C.sub.13 H.sub.12 O.sub.6 Cl.sub.2     (Mw 319, 144) IRνmax(Nujol) 3500˜2300(b), 1760, 1645  C H Cl     NMR(d.sub.6 -acetone) 8.5˜6.8(1H,b), 7.26(1H,s), 5.33 C; 48.93     3.79 22.22  (1H, t, J = 3), 4.78, 4.51( 1H, dd, J = 3.13), 3.42(1H, F;     49.08 3.73 22.45  m), 1.07(6H, dd, J =      10.7) 5 5 2 n-butyl H 151˜152  C.sub.14 H.sub.14 O.sub.5 Cl.sub.2     (Mw 333, 171) IRνmax(Nujol) 3500˜2300(b), 1738, 1675  C H Cl     NMR(d.sub.6 -acetone) 8.0˜6.8(1H,b), 7.34(1H,s), 5.31 C; 50.47     4.24 21.28  (1H, t, J = 3), 4.78, 4.52( 1H, dd, J =      3.13), 1.77˜1.06 F; 50.23 4.21 21.28  (2 × 2H), 0.88(3H, t,     J = 7) 6 5 2 cyclopentyl H 149˜150 C.sub.15 H.sub.14 O.sub.5     Cl.sub.2 (Mw 345, 182 IRνmax(Nujol) 3550˜2200(b), 1722, 1672  C H      Cl  NMR(d.sub.6 -acetone) 7.26(1H,s), 6.0˜4.9(1H,b), 5.29 C;     52.19 4.09 20.54  (1H, t, J = 3), 4.76, 4.48( 1H, dd, J = 3.13),     3.65(1H, F; 52.13 4.01 20.56  m), 1.85˜1.57(8H) 7 5 2 benzyl H     171˜173 C.sub.17 H.sub.12 O.sub.5 Cl.sub.2      (Mw 367, 189) IRνmax(Nujol) 3300˜2400(br), 1730, 1683  C H Cl  N     MR(d.sub.6 -acetone) 7.7˜6.8(1H,br), 7.30(1H,s), C; 55.61 3.29     19.31  7.22(5H,s), 5.30(1H, t, J = 3), 4.71, 4.48(2 × 1H, dd, J =     F; 55.93 3.35 19.25  3.13), 4.25(2H,s) 8 5 2 phenyl H 218˜219     C.sub.16 H.sub.10 O.sub.5 Cl.sub.2 (Mw 353, 161) IRνmax(Nujol)     3500˜2200(b), 1760, 1630  C H Cl  NMR(d.sub.6      -acetone) 8.7˜7.7(1H,b), 7.83˜7.35(5H), C; 54.42 2.85 20.08      7.13(1H,s), 5.27(1H, t, J = 3) 4.48, 4.21( 1H, dd, J = 3.13) F; 54.35     3.13 19.99 9 5 2 O--chlorophenyl H 214˜215 C.sub.16 H.sub.9     O.sub.5 Cl.sub.2 (Mw 387, 606) IRνmax(Nujol) 3600˜2300(br),     1758, 1622  C H Cl  NMR(d.sub.6 -acetone) 10.3˜9.0(1H,b,), ca.     7.46(4H), C; 49.58 2.34 27.44  7.33(1H,s), 5.22(1H, t, J = 3), 4.41,     4.22(2 × 1H, dd, J =      3.12) F; 49.76 2.53 27.67 10 5 2 m-chlorophenyl H 176˜177     C.sub.16 H.sub.9 O.sub.5 Cl.sub.2 (Mw 387, 606) IRνmax(Nujol)     3600˜2000(br), 1760, 1640  C H Cl  NMR(d.sub.6      -acetone) 7.77˜7.30(4H), 8.5˜7.1(1H,br), 7 C; 49.58 2.34     27.44  .17(1H,s), 5.27(1H, t, J = 3), 4.51, 4.32(2 × 1H, dd, J =     3.12) F; 49.68 2.62 27.11 11 5 2 p-chlorophenyl H 241˜242 C.sub.16     H.sub.9 O.sub.5 Cl.sub.2      (Mw 387, 606) IRνmax(Nujol) 3600˜2400(br), 1768, 1642  C H Cl  N     MR(d.sub.6 -acetone) 8.1˜6.7(1H,br), 7.81, 7.52(2 × C; 49.58     2.34 27.44  2H, d, J = 9), 7.17(1H,s), 5.29(1H, t, J = 3), 4.53, 4.33 F;     49.67 2.60 27.25  (2 × 1H, dd, J = 3.12) 12 5 2 o-fluorophenyl H     225˜227 C.sub.16 H.sub.9 O.sub.5 Cl.sub.2      F(Mw 371, 151) IRνmax(Nujol) 3160˜3060(br), 1760, 1620  C H Cl F      NMR(d.sub.6 -acetone) 7.74˜7.04(4H), 7.27(1H,s), ca. C; 51.78     2.44 19.10 5.12 6.26(1H), 5.23(1H, t, J = 3), 4.45, 4.25( 1H, dd, J =     3.13) F; 51.85 2.56 19.01 5.09 13 5 2 o-tolyl H 212˜213 C.sub.17     H.sub.12 O.sub.5 Cl.sub.2      (Mw 367, 189) IRνmax(Nujol) 3600˜2200(br), 1758, 1620  C H Cl  N     MR(d.sub.6 -acetone) 9.3˜7.8(1H,br), 7.53˜7.26(4H), 7 C;     55.61 3.29 19.31  .19(1H,s), 5.25(1H, t, J = 3), 4.46, 4.27(2 ×     1H, dd, J = 3.12), F; 56.32 3.42 18.79  2.46(3H,s) 14 5 2 m-tolyl H     194˜195 C.sub.17 H.sub.12 O.sub.5 Cl.sub.2      (Mw 367, 189) IRνmax(Nujol) 3500˜2100(br), 1765, 1637  C H Cl  N     MR(d.sub.6 -acetone) 10.1˜8.7(1H,br), 7.61˜7.31 C; 55.61     3.29 19.31  (4H), 7.11(1H,s), 5.26(1H, t, J = 3), 4.49, 4.30(2 ×     1H, F; 55.44 3.40 19.22  dd, J = 3.12), 2.35(3H,s) 15 5 2 p-tolyl H     212˜214 C.sub.17 H.sub.12 O.sub.5 Cl.sub.2      (Mw 367, 189) IRνmax(Nujol) 3400˜2100(br), 1755, 1623  C H Cl  N     MR(d.sub.6 -acetone) 9.4˜7.4(1H,br), 7.67, 7.27(2 × C; 55.61     3.29 19.31  2H, d, J = 8), 7.09(1H,s), 5.26(1H, t, J = 3), 4.48, 4.30 F;     55.68 3.34 19.19  (2 × 1H, dd, J = 3.12), 2.38(3H,s) 16 5 2     2-thienyl H 215˜217 C.sub.14 H.sub.6 O.sub.5 Cl.sub.2 S(Mw 359,     187) IRνmax(Nujol) 3400˜2000(b), 1765, 1620  C H Cl S NMR(d.sub.     6 -acetone) 8.8˜7.8(1H,b), 7.94(1H, dd, J = C;46.822.2419.748.93     1.5,5.5),7.53(1H, dd,J = 1.5,4.5), 7.15(1H,d, d. J = F; 47.10 2.65 19.41     8.52 4.5, 5.5), 7.15(1H,s), 5.28(1H, t, J = 3), 4.58, 4.37      ( 1H,     dd, J = 3.13) 17 5 2 2-furyl H 160˜162 C.sub.14 H.sub.6 O.sub.5     Cl.sub.2 (Mw 343, 122) IRνmax(Nujol) 3140, 1760, 1638, 1585  C H Cl     NMR(d.sub.6 -acetone) 8.5˜7.5(1H,b), 7.87(1H, dd, J = ; 49.01 2.35     20.66  0.5, 2.0), 7.19(1H,s), 7.18(1H, dd, J = 0.5, 2.0), 6.66 ; 49.41     2.70 20.43  (1H, dd, J = 2.0, 4.0), 5.31(1H, t, J = 3), 4.61, 4.39     (2 × 1H, dd, J = 3) 18 5 3 Et H 173˜175 C.sub.12 H.sub.10     O.sub.5 Cl.sub.2 (Mw 305, 113) IRνmax(Nujol) 3080, 1740, 1715, 1682,     1580  C H Cl  NMR(d.sub.6 -acetone) 8.33˜7.50(1H,b), 7.40(1H,s),     C; 47.24 3.30 23.24  5.37(1H, t, J = 3), 4.43˜4.95(2H,m), 3.08(2H,     q, J = 7), F; 47.17 3.46 23.18  1.10(3H, t, J = 7) 19 5 3 2-thienyl H     non- C.sub.14 H.sub.6 O.sub.5 Cl.sub.2 S(Mw 359, 187) IRνmax(Nujol)     3600˜2200(br), 1730, 1630      crystal Mass M.sup.+      358 NMR(d.sub.6 -acetone) 9.0˜8.0(1H,br), 7.94(1H, dd, J =     1.5, 5.5), 7.78(1H, dd, J = 1.5, 4.5), 7.17(1H,s), 7.16        (1H, dd,     J = 4.5, 5.5), 5.12(1H, t, J = 3), 4.78, 4.47(2 ×        1H, dd, J     = 3) 20 6 2 H H 262˜263 C.sub.10 H.sub.6 O.sub.5 Cl.sub.2 (Mw 277,     059) IRνmax(Nujol) 1755, 1658, 1593, 1558  C H Cl  NMR(d.sub.6     -acetone) 10.33(1H,s), 7.35(1H,s), 5.40 C; 43.35 2.18 25.59  (1H, t, J =     3), 4.75˜4.33(2H,m) F; 43.07 2.36 25.53 21 6 2 Me H 199˜200     C.sub.11 H.sub.6 O.sub.5 Cl.sub.2 (Mw 291, 090) IRνmax(Nujol)     3400˜2100(br), 1763, 1680, 1665  C H Cl  NMR(d.sub.6 -acetone)     7.16(1H,s), 7.1˜6.5(1H,br), C; 45.39 2.77 24.36  5.31(1H, t, J =     3), 4.68, 4.41(2 × 1H, dd, J = 13.3), 2.56 F; 45.11 2.92 24.09     (3H,s) 22 6 2 Et H 177˜179 C.sub.12 H.sub.10 Cl.sub.2 O.sub.5 (Mw     305, 113) IRνmax(Nujol) 1754, 1710, 1600  C H Cl  NMR(d.sub.6     -acetone) 7.09(1H,s), 4.78˜4.33(2H,m), C; 47.24 3.30 23.24     2.92(2H, q, J = 7), 1.11(3H, t, J = 7) F; 47.02 3.07 23.45 23 6 2     n-propyl H 132˜133 C.sub.13 H.sub.12 O.sub.5 Cl.sub.2 (Mw 319,     144) IRνmax(Nujol) 3600˜2000(br), 1740, 1700  C H Cl  NMR(CDCl.s     ub.3) 9.52(1H,s), 6.97(1H,s), 5.07(1H, t, J = C; 48.93 3.79 22.22  3),     4.58, 4.32(2 × 1H, dd, J = 3.13), 2.87(2H, t, J = 7), F; 48.63     3.59 22.12  1.70(2H,m), 0.96(3H, t, J = 7) 24 6 2 n-butyl H oil C.sub.14     H.sub.14 O.sub.5 Cl.sub.2      (Mw 333, 171) IRνmax(CHCl.sub.3) 3600˜2400(br), 1738, 1690        NMR(CDCl.sub.3) 8.20(1H,br), 6.94(1H,s), ca. 5.04(1H),     4.63˜4.21(2H), 2.87(2H, t. J = 7), 1.82˜1.11(2 × 2H),           0.91(3H, t, J = 7) 25 6 2 phenyl H 201˜204 C.sub.16 H.sub.10     Cl.sub.2 O.sub.5 (Mw 353, 157) IRνmax(Nujol) 3160, 1760, 1650  C H Cl      NMR(d.sub.6 -acetone) 7.87˜7.33(5H,m), 6.95(1H,s), C; 54.42 2.85     20.08  5.32(1H, t, J = 3), 4.83˜4.30(2H,m) F; 54.13 2.93 20.36 26     6 2 o-chlorophenyl H 149˜150 C.sub.16 H.sub.9 O.sub.5 Cl.sub.3 (Mw     387, 606) IRνmax(Nujol) 3600˜2200(br), 1723, 1675       Mass     M.sup.+  386 NMR(d.sub.6 -acetone) 11.0˜9.3(1H,br), ca. 7.51(4H),           7.01(1H,s), 5.33(1H, t, J = 3), 4.68, 4.42(2 × 1H, dd, J =     3.12) 27 6 2 m-chlorophenyl H 198˜200 C.sub.16 H.sub.9 O.sub.5     Cl.sub.3 (Mw 387, 606) IRνmax(Nujol) 3600˜2000(br), 1758, 1667  C      H Cl  NMR(d.sub.6 -acetone) 8.8˜7.7(1H,br), 7.76˜7.43(4H),     7.01 C; 49.58 2.34 27.44  (1H,s), 5.33(1H, t, J = 3), 4.69, 4.45(2     × 1H, dd, J = 3.12) F; 49.47 2.48 27.25 28 6 2 p-chlorophenyl H     152˜154 C.sub.16 H.sub.9 O.sub.5 Cl.sub.3      (Mw 387, 606) IRνmax(Nujol) 3650˜2200(br), 1765, 1660  C H Cl  N     MR(d.sub.6 -acetone) 7.77, 7.53(2 × 2H, d, J = 9), 7.4˜6.3     C; 49.58 2.34 27.44  (1H,br), 6.96(1H,s), 5.30(1H, t, J = 3), 4.67,     4.42(2 × 1 F; 49.26 2.67 27.21  H, dd, J =      3.12) 29 6 2 o-fluorophenyl H 197˜199 C.sub.16 H.sub.9 O.sub.5     Cl.sub.2 F(Mw 371, 151) IRνmax(Nujol) 3600˜2100(br), 1720, 1680      C H Cl F NMR(d.sub.6      -acetone) 8.5˜7.0(1H,br), 7.80˜7.12(4H, C; 51.78 2.44 19.10     5.12 m), 7.03(1H,s), 5.33(1H, t, J = 3), 4.70, 4.45(2 × 1H, dd, J     = 3.13) F; 51.52 2.64 19.30 5.16 30 6 2 2-thienyl H 192˜194     C.sub.14 H.sub.5 O.sub.6 Cl.sub.2 S(Mw 359, 184) IRνmax(Nujol) 3475,     3400, 1720, 1710, 1620  C H S Cl NMR(d.sub.6 -acetone) 8.00(1H, dd, J =     5.1), 7.50(1H, dd, J = 5.1), C; 46.81 2.25 8.93 19.74 7.17(1H, t, J =     5), 7.03(1H, s), 5.30(1H, t, J = 4), F; 46.88 2.36 8.9       19.58 4.30˜4.83(2H, m) 31 6 2 2-furyl H 142˜145 C.sub.14     H.sub.6 O.sub.5 Cl.sub.2.H.sub.2 O(Mw 361, 138) IRνmax(Nujol) 3480,     3410, 1720, 1650  C H Cl  NMR(d.sub.6 -acetone) 7.88(1H, dd. J = 0.5,     2.0), 7.16 C; 46.56 2.79 19.63  (1H, dd, J = 0.5, 4.0), 7.04(1H,s),     6.67(1H, dd, J = 2.0, F; 47.30 2.84 19.62  4.0), ca. 5.80(1H), 5.30(1H,     t, J = 3), 4.68, 4.42(2 ×      1H, dd, J = 3.13) 32 6 2 cyclohexyl H      oil C.sub.16 H.sub.18 O.sub.5 Cl.sub.2      (Mw 359, 209) IRνmax(CHCl.sub.3) 3600˜2300(br), 1735, 1690       Mass M.sup.+ 358 NMR(CDCl.sub.3) 7.73(1H,br,s), 6.82(1H,s), 5.03(1H,     t,        J = 3), 4.56, 4.29(2 × 1H, dd, J = 3.12), ca. 2.98(1H),           1.95˜1.24(OH) 33 6 2 o-tolyl H 187˜188 C.sub.17     H.sub.12 O.sub.5 Cl.sub.2      (Mw 367, 189) IRνmax(Nujol) 3500˜2300(br), 1758, 1645  C H Cl  N     MR(d.sub.6 -acetone) 10.0˜8.5(1H,br), 7.57˜7.16 C; 55.61     3.29 19.31  (4H), 6.96(1H,s), 5.33(1H, t, J = 3), 4.69, 4.44(2 ×     1H, F; 55.59 3.33 19.47  dd, J = 3.12), 2.49(3H,s) 34 6 2 m-tolyl H     205˜206 C.sub.17 H.sub.12 O.sub.5 Cl.sub.2      (Mw 367, 189) IRνmax(Nujol) 3210˜3180, 1760, 1652  C H Cl     NMR(d.sub.6 -acetone) 10.4˜8.9(1H,br), 7.63˜7.23 C; 55.61     3.29 19.31  (4H), 6.93(1H,s), 5.31(1H, t, J = 3), 4.68, 4.44(2 ×     1H, F; 55.71 3.34 19.06  dd, J =  3.12), 2.37(3H,s) 35 6 2 p-tolyl H     188˜189 C.sub.17 H.sub.12 O.sub.5 Cl.sub.2      (Mw 367, 189) IRνmax(Nujol) 3400˜2100(br), 1750, 1640  C H Cl  N     MR(d.sub.6 -acetone) 9.5˜8.3(1H,br), 7.64, 7.30(2 × C; 55.61     3.29 19.31  2H, d, J = 8), 6.89(1H,s), 5.28(1H, t, J = 3), 4.66, 4.42 F;     55.53 3.33 19.35  (2 × 1H, dd, J = 3.12), 2.37(3H,s) 36 6 3     n-propyl H 124˜125 C.sub.13 H.sub.12 O.sub.5 Cl.sub.2 (Mw 319,     144) IRνmax(Nujol) 3600˜2200(br), 1710, 1690  C H Cl  NMR(CDCl.s     ub.3) 9.65(1H,s), 7.07(1H,s), 4.94(1H, t, J = 3), C; 48.93 3.79 22.22     4.67, 4.46(2 × 1H, dd, J = 3.13), 2.87(2H, t, J = 7), F; 48.84     3.54 22.20  1.91˜1.50(2H,m), 0.95(3H, t, J =      7) 37 6 3 o-etoxyphenyl H 206˜208 C.sub.13 H.sub.14 O.sub.5     Cl.sub.2 (Mw 397, 215) IRνmax(Nujol) 3600˜2200(br), 1750, 1643  C      H Cl  NMR(d.sub.6 -acetone) 7.78˜6.93(4H,m), 6.95(1H,s), C; 54.43     3.55 17.85  7.4˜6.0(1H,br), 5.17(1H, t, J = 3), 4.76, 4.50(2     × 1H, F; 54.27 3.54 17.74  dd, J = 3.13), 3.90(2H, q, J = 7),     0.93(3H, t, J = 7) 38 6 3 o-fluorophenyl H 162˜163 C.sub.16     H.sub.9 O.sub.5 Cl.sub.2      F(Mw 371, 151) IRνmax(Nujol) 3600˜2200(br), 1758, 1630  C H Cl F      NMR(d.sub.6 -acetone) 9.4˜7.3(1H,br), 7.83˜7.23(4H, C;     51.78 2.44 19.10 5.12 m), 7.15(1H,s), 5.12(1H, t, J = 3), 4.79, 4.58(2     × 1H, F; 51.55 2.65 19.65 4.95 dd, J = 3.13) 39 6 3 phenyl H     207˜209 C.sub.16 H.sub.10 Cl.sub.2 O.sub.5      (Mw 353, 157) IRνmax(Nujol) 1720, 1670, 1590  C H Cl  NMR(d.sub.6     -acetone) 8.22˜7.48(5H,m), 7.07(1H,s), C; 54.42 2.85 20.08     5.22(1H, t, J = 3), 4.95˜4.45(2H,m) F; 54.19 3.03 20.23 40 6 3     2-thienyl H 220˜222 C.sub.14 H.sub.6 O.sub.5 Cl.sub.2 S(Mw 359,     184) IRνmax(Nujol) 1730, 1620, 1600  C H Cl S NMR(d.sub.6 -acetone)     8.03(1H, dd, J = 5.1), 7.53(1H, dd, J = 5.1), C; 46.81 2.25 19.74 8.93     7.23(1H, t, J = 5), 7.17(1H,s), 5.23(1H, t, J = 4), F; 46.74 2.56 19.80     8.85 4.68(2H, t, J = 4) 41 5 2 Et Et 108˜109 C.sub.14 H.sub.14     O.sub.5 Cl.sub.2 (Mw 333, 171) IRνmax(Nujol) 1735, 1670, 1580  C H Cl      NMR(d.sub.6 -acetone) 7.34(1H,s), 5.29(1H, t, J = 3), C; 50.47 4.24     21.28  4.75, 4.48(2 × 1H, dd, J = 3.13), 4.21, 2.91(2 × 2H,     q, J = 8), F; 50.35 4.33 21.54  1.23, 1.07(2 × 3H, t, J = 8) 42 5     2 phenyl Et 171˜ 172 C.sub.18 H.sub.14 O.sub.5 Cl.sub.2 (Mw 381,     216) IRνmax(Nujol) 1742, 1658  C H Cl  NMR(d.sub.6      -acetone) 7.85˜7.42(5H), 7.16(1H,s), 5.29 C; 56.71 3.70 18.60     (1H, t, J = 3), 4.49, 4.31(2 × 1H, dd, J = 3.12), 4.22(2H, F;     56.34 3.81 18.62  q, J = 7), 1.20(3H, t, J = 7) 43 5 2 2-thienyl Et     124˜125 C.sub.16 H.sub.12 O.sub.5 Cl.sub.2      S(Mw 387, 237) IRνmax(Nujol) 1745, 1640, 1582, 1570  C H Cl S     NMR(CDCl.sub.3) 7.72(1H, dd, J = 6.2), 7.47(1H, dd, J = 6.2), C; 49.63     3.12 18.31 8.28 7.10(1H, t, J = 6), 7.17(1H,s), 5.00(1H, t, J = 4), F;     49.30 3.28 18.33  4.62˜4.17(2H,m), 4.27(2H, q, J = 8), 1.27(3H, t,     J = 8) 44 5 3 Et Et 73˜74 C.sub.14 H.sub.14 O.sub.5 Cl.sub.2 (Mw     333, 167) IRνmax(Nujol) 3080, 1740, 1678, 1582  C H Cl  NMR(d.sub.6     -acetone) 7.33(1H,s), 5.30(1H, t, J =      4), C; 50.47 4.24 21.28  4.72˜4.40(2H,m), 4.23(2H, q, J = 8),     3.05(2H, q, J = 8), F; 50.29 4.26 21.31  1.23(3H, t, J = 8), 1.15(3H, t,     J = 8) 45 6 3 o-fluorophenyl Et 139˜140 C.sub.13 H.sub.13 O.sub.5     Cl.sub.2 F(Mw 399, 206) IRνmax(Nujol) 1775, 1670, 1605  C H Cl F     NMR(CDCl.sub.3) 7.82˜6.98(4H,m), 7.10(1H,s), 4.86(1H, C; 54.16     3.28 17.76 4.76 t, J = 3), ca. 4.53(2H), 4.27(2H, q, J = 7), 1.27(3H, t,     J = 7) F; 53.93 3.36 17.76 4.78 46 6 3 phenyl Et 112˜113 C.sub.18     H.sub.14 Cl.sub.2 O.sub.5 (Mw 381, 211) IRνmax(Nujol) 1743, 1667,     1600, 1557  C H Cl  NMR(d.sub.6      -acetone) 7.05(1H,s), 7.88˜7.47(5H,m), C; 56.71 3.10 18.60     5.20(1H, t, J = 4.0), 4.90˜4.43(2H,m), 4.23(2H, q, J = 7.0), F;     56.66 3.60 18.57  1.23(3H, t, J = 7.0) 47 6 3 2-thienyl Et 137˜138 C     .sub.16 H.sub.12 O.sub.5 Cl.sub.2 S(Mw 387, 237) IRνmax(Nujol) 1750,     1658, 1588  C H S Cl NMR(d.sub.6 -acetone) 7.23(1H,s), 8.10(1H, dd, J =     5.0, C; 49.63 3.12 8.28 18.31 1.0), 7.58(1H, dd), 7.30(1H, t, J = 5.0),     5.27(1H, t, J = 4.0), F; 49.65 3.10 8.06 18.19 4.70(2H, t, J = 4.0),     4.30(2H, q, J = 7.0), 1.27      (3H, t, J = 7.0) 48 6 2 phenyl Et     71˜73 C.sub.18 H.sub.14 O.sub.5 Cl.sub.2      (Mw 381, 211) NMR(CDCl.sub.3) 5.80(1H,s), 7.90, 7.17(5H,m), 5.00(1H,  C H      Cl  t, J = 5.0) ca. 4.43(2H,m), 4.27(2H, q, J = 7.0), 1.30 C; 56.71     3.70 18.60  (3H, t, J = 7.0) F; 56.56 3.83 18.57 49 6 2 2-thienyl Et      134˜135 C.sub.18 H.sub.12 O.sub.5 Cl.sub.2 S(Mw 387, 237)     NMR(d.sub.6 -acetone) 7.01(1H,s), 8.03(1H, dd, J = 5.0,  C H Cl  1.0),     7.52(1H, dd, J = 5.0, 1.0), 7.22(1H, t, J = 5.0) C; 49.63 3.12 8.28     18.31 5.33(1H, t, J = 4.0), 4.33˜4.87(2H,m), 4.27(2H, q, J = 7.0),     F; 49.46 3.25 8.24 18.15 1.27(3H, t, J =      7.0)

EXAMPLE 4 ##STR17##

A solution of 1.500 g of the compound (Ib'-43), 2.500 g ofN-bromosuccinimide (about 3.5 equivalent) and 230 mg of benzoyl peroxidedissolved in 80 ml of dry carbon tetrachloride is refluxed for about 20hours. After removal of the precipitate by filtration, the filtrate isevaporated under reduced pressure to give a residue, 3.0 g Of sodiumiodide and 100 ml of acetone are added to the residue, and the mixtureis refluxed for 1.5 hours. The reaction mixture is filtered in order toremove the precipitate and then the filtrate is evaporated under reducedpressure, and extracted three times with dichloromethane. The organiclayer is washed twice with an aqueous solution of sodium thiosulfate,then with water, dried over sodium sulfate and evaporated to give 1.80 gof a residue, which is recrystallized from ethanol to give 1.100 g ofthe objective 2-epoxycarbonyl-5-thenoyl-7,8-dichloro-1,4-benzodioxine(Ib"-1). Yield 73%, mp. 165°-166° C.

Anal. Calcd. (%) for C₁₆ H₁₀ O₅ Cl₂ S (MW. 385.221): C 49.89, H 2.62, Cl18.41, S 8.32 Found (%): C 49.91, H 2.75, Cl 18.70, S 8.32.

IR(Nujol) νmax: 3150, 3100, 1735, 1690, 1675, 1630, 1599, 1575 cm⁻¹.

NMR(CDCl₃) δppm: 7.77(1H, d, d, J=6.2), 7.53(1H, d, d, J=6.2), 7.12(1H,t, J=6.2), 7.12(1H, s,), 6.90(1H, s), 4.27(2H, q, J=8), 1.47(3H, t,J=8).

To a solution of 742 mg of the compound (Ib"-1) dissolved in 10 ml ofdioxane, is added 3 ml of 1N sodium hydroxide. The mixture is heated at70°-80° C. for 5-10 minutes and then allowed to stand for 1 hour. Afterneutralized with hydrochloric acid, the reaction mixture is extractedtwice with ethyl acetate. The organic layer is washed twice with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, and evaporated to give 650 mg of a residue, which isrecrystallized from dichloromethane-petroleum ether to give 535 mg of2-carboxy-5-thenoyl-7,8-dichloro-1,4-benzodioxine. (Ib"-2). Yield 77.8%,mp. 233°-236° C.

Anal. Calcd. (%) for C₁₄ H₆ O₅ Cl₂ S (MW. 357.167): C 47.08, H 1.69, Cl19.85, S 8.98, Found (%): C 46.92, H 1.95, Cl 19.85, S 8.79.

IR(Nujol) νmax: 3120, 1718, 1660, 1590, 1565 cm⁻¹.

NMR(d₆ -acetone) δppm: 8.03(1H, d, d, J=6.2), 7.77(1H, d, d, J=6.2),7.25(1H, d, d, J=6), 7.27(1H, s), 7.10(1H, s), 7.00-6.37(1H, b).

General Method ##STR18##

A solution of 1.5 g of a compound (Ib'), about 3.5 equimole ofN-bromosuccinimide, and 200-250 mg of benzoyl peroxide dissoved in 80 mlof dry carbon tetrachloride is heated for 20 hours. After removal of theprecipitate by the filtration, the filtrate is evaporated under reducedpressure to give a residue, to which, 3 g of sodium iodide and 100 ml ofacetone is added. The mixture is refluxed for about 1-2 hours, and thenworked up in a usual manner (washed with sodium thiosulfate to removeBr₂) to give a compound (Ib") (R₅ =R₄). To a solution of the compound intetrahydrofuran or dioxane is added an aqueous solution of sodiumhydroxide. The mixture is heated on a bath at 70° C. for 5 to 10minutes, then allowed to stand for an hour, neutralized withhydrochloric acid and poured into water. Treatment in a conventionalmanner gives a compound Ib" (R₅ =H). Compounds prepared in the samemanner as above and their physical constants are shown in Table 9.

                                      TABLE 9                                     __________________________________________________________________________         Position                                                                           Position                                                            Compd.                                                                             of   of              mp.  Elementary Anal.                                                                            IR(cm.sup.-1)                    I a-b'                                                                             --COR.sub.2                                                                        --COOR.sub.4                                                                        R.sub.2 R.sub.4                                                                         °C.                                                                         C; Calcd. (%), F; Found (%)                                                                 NMR(δ,                     __________________________________________________________________________                                                 Hz)                              3    5    2     phenyl  Et                                                                              153˜155                                                                      C.sub.16 H.sub.12 O.sub.5 Cl.sub.2 (Mw                                        379, 200)     IRνmax(Nujol) 1735, 1685,                                                  1659                                                              C  H  Cl    NMR(d.sub.6 -acetone)                                                         7.97˜7.44(5H),                                            C;                                                                              57.02                                                                            3.19                                                                             18.70 7.24, 7.02(2 × 1H,s),                                     F;                                                                              56.51                                                                            3.33                                                                             19.56 4.24(2H, q, J = 7), 1.26(3H,                                                  t, J = 7)                        4    5    2     phenyl  H 265˜268                                                                      C.sub.16 H.sub.8 O.sub.5 Cl.sub.2 (Mw 351,                                    145)          IRνmax(Nujol)                                                  C  H  Cl    3500˜2000(br), 1690,                                                    1660                                                            C;                                                                              54.73                                                                            2.30                                                                             20.19 NMR(DMSO-d.sub.6)                                                             7.93˜7.48(5H),                                            F;                                                                              54.65                                                                            2.53                                                                             20.02 7.35, 7.17(2 × 1H,s)       5    6    3      o-fluorophenyl                                                                       Et                                                                              169˜171                                                                      C.sub.16 H.sub.11 O.sub.5 Cl.sub.2 F(Mw                                       397, 185)     IRνmax(Nujol) 1770, 1675,                                                  1645,                                                             C  H  Cl F  1600, 1520                                                      C;                                                                              54.43                                                                            2.79                                                                             17.85                                                                            4.78                                                                             NMR(CDCl.sub.3) 6.85, 7.02(2                                                  × 1H,s),                                                  F;                                                                              54.14                                                                            2.90                                                                             17.75                                                                            4.82                                                                             7.83˜6.83(4H,m),                                                        4.27(2H, q, J = 7.0),                                                         1.32(3H, t, J = 7.0)             6    6    3     o-fluorophenyl                                                                        H 238˜239                                                                      C.sub.16 H.sub.7 O.sub.5 Cl.sub.2 F(Mw                                        369, 131)     IRνmax(Nujol) 1690,                                                        1660,                                                             C  H  Cl F  1605, 1570                                                      C;                                                                              52.06                                                                            1.91                                                                             19.21                                                                            5.17                                                                             NMR(d.sub.6 -acetone) 6.97,                                     F;                                                                              51.96                                                                            2.24                                                                             19.51                                                                            5.22                                                                             7.27(2 × 1H,s),                                                         7.97˜7.00(4H,m)            7    6    3     phenyl  Et                                                                              155˜157                                                                      C.sub.16 H.sub.12 O.sub.5 Cl.sub.2 (Mw                                        379, 195)     IRνmax(Nujol) 1720,                                                        1660,                                                             C  H  Cl    1590, 1575                                                      C;                                                                              57.01                                                                            3.19                                                                             18.07 NMR(CDCl.sub.3) 6.82,                                           F;                                                                              57.22                                                                            3.26                                                                             18.59 7.07(2 × 1H,s),                                                         7.90˜7.30(5H,m),                                                        4.30(2H, q, J = 7.0),                                                         1.32(3H, t, J = 7.0)             8    6    3     phenyl  H 250˜252                                                                      C.sub.16 H.sub.8 O.sub.5 Cl.sub.2 (Mw 351,                                    141)          IRνmax(Nujol) 1700,                                                        1678,                                                             C  H  Cl    1660, 1595, 1575                                                C;                                                                              54.73                                                                            2.30                                                                             20.19 NMR(d.sup.6 -DMSO) 7.07,                                        F;                                                                              54.39                                                                            2.53                                                                             19.96 7.35(2 × 1H,s),                                                         7.93˜7.43(5H,m)            9    6    3     2-thienyl                                                                             Et                                                                              171˜173                                                                      C.sub.16 H.sub.13 O.sub.5 Cl.sub.2 S(Mw                                       385, 221)     NMR(CDCl.sub.3) 6.83, 7.02(2                                                  × 1H,s),                                                    C  H  Cl S  7.05(1H, t, J = 4.0),                                           C;                                                                              49.89                                                                            2.62                                                                             18.41                                                                            8.32                                                                             7.45(1H, dd, J = 4.0, 1.0),                                     F;                                                                              49.69                                                                            2.74                                                                             18.38                                                                            8.13                                                                             7.77(1H, dd, J = 4.0, 1.0),                                                   4.28(2H, q, J = 7.0),                                                         1.32(3H, t, J = 7.0)             10   6    3     2-thienyl                                                                             H 281˜ 283                                                                     C.sub.14 H.sub.6 O.sub.5 Cl.sub.2 S(Mw                                        357, 167)     IRνmax(Nujol) 1700,                                                        1660,                                                             C  H  Cl S  1642, 1600, 1570                                                C;                                                                              47.08                                                                            1.69                                                                             19.85                                                                            8.98                                                                             NMR(d.sup.6 -DMSO) 7.13,                                        F;                                                                              46.87                                                                            2.12                                                                             20.04                                                                            8.71                                                                             7.37(2 × 1H,s),                                                         7.30(1H, t, J = 5.0),                                                         7.60(1H, dd, J = 5.0, 1.0),                                                   8.17(1H, dd, J = 5.0, 1.0)       11   6    2     phenyl  Et                                                                              95˜96                                                                        C.sub.16 H.sub.12 O.sub.5 Cl.sub.2 (Mw                                        379, 195)     IRνmax(Nujol) 1725,                                            C  H  Cl    1670, 1595, 1570                                                C;                                                                              57.01                                                                            3.19                                                                             18.70 NMR(CDCl.sub.3) 6.68(1H,s),                                     F;                                                                              56.41                                                                            3.26                                                                             19.00 6.97(1H,s),                                                                   7.27˜7.92(5H,m),                                                        4.33(2H, q, J = 7.0),                                                         1.33(3H, t, J = 7.0)             12   6    2     2-thienyl                                                                             Et                                                                              126˜127                                                                      C.sub.16 H.sub.10 O.sub.5 Cl.sub.2 S(Mw                                       385, 221)     IRνmax(Nujol) 1725,                                            C  H  Cl  S 1670, 1645, 1600, 1570                                          C;                                                                              49.89                                                                            2.62                                                                             18.41                                                                            8.32                                                                             NMR(d.sub.6 -acetone)                                           F;                                                                              49.86                                                                            2.92                                                                             18.45                                                                            8.23                                                                             1.30(3H, t, J = 7.0),                                                         4.25(2H, q, J = 7.0),                                                         7.00(1H,s), 7.20(1H,s),                                                       7.23(1H, t, J = 5.0), 7.60                                                    (1H, dd, J = 5.01, 1.0),                                                      8.03(1H, dd)                     13   6    2     2-thienyl                                                                             H 274˜276                                                                      C.sub.14 H.sub.6 O.sub.5 Cl.sub.2 S(Mw                                        357, 167)     IRνmax(Nujol) 1705,                                            C  H  Cl S  1670, 1640, 1570                                                C;                                                                              47.08                                                                            1.69                                                                             19.85                                                                            8.98                                                                             NMR(d.sub.6 -acetone)                                           F;                                                                              46.99                                                                            2.00                                                                             19.86                                                                            9.02                                                                             6.95, 7.17(2 × 1H,s),                                                   7.18(1H, t, J = 0.5),                                                         7.55(1H, dd, J = 5.0, 1.0),                                                   7.98(1H, dd, J = 5.0,            __________________________________________________________________________                                                 1.0)                         

EXAMPLE 5 ##STR19##

To a solution of 39.5 g (0.281 mol) of benzoyl chloride dissolved in 118ml of dry dichloroethane is added 46.83 g (0.351 mol) of aluminiumchloride. A solution of 15.712 g (0.088 mol) of the starting material(II) in dry dichloroethane (197 ml) is dropwise added to the mixturewhile being stirred for about 20 minutes and then the reaction mixtureis refluxed for about 20 hours. After cooled, the mixture is poured intoice-water/conc. hydrochloric acid whereby the aluminium chloride isdecomposed. The resulting mixture is extracted 3 times with ethyl etherand the organic layers are washed twice with a saturated solution ofsodium chloride, dried over sodium sulfate, and evaporated under reducedpressure to give a residue (51.10 g).

A mixture of the residue, 210 ml of ethanol, and 210 ml of 2N-sodiumhydroxide is refluxed for 30 minutes, evaporated under reduced pressure,neutralized by the addition of hydrochloric acid, and the resultingmixture is extracted twice with ethyl ether. The organic layers arewashed with water, dried over sodium sulfate, and evaporated to drynessto give a residue, which is recrystallized fromdichloromethane/petroleum ether to give 20.824 g (yield 83%) of thetitled compound (IV-1), m.p. 178°-180° C.

Anal. Calcd. (%) for C₁₃ H₈ Cl₂ O₃ : C; 55.15, H; 2.85, Cl; 25.05, Found(%): C; 55.05; H; 2.98, Cl; 25.30.

IR(Nujol) νmax: 3425, 3100, 1655, 1595, 1580 cm⁻¹.

NMR(d⁶ -acetone) δppm: 6.95 (1H, s), 7.93-7.50 (5H, m).

Process 1' (General Procedure): ##STR20##

A mixture of the starting material (II) (0.01 mol), R² COCl (0.04-0.03mol), and AlCl₃ (0.025-0.03 mol) in 350 ml of dichloroethane is refluxedfor about 20 hours and poured into ice-water/conc. hydrochloric acid.The mixture is extracted with ethyl ether or ethyl acetate. The organiclayer is combined with 250 ml of ethanol and 250 ml of 2N-sodiumhydroxide, and the mixture is then refluxed for about 30 minutes to givea 5-acyl compound (IV). Thus prepared compounds and their physicalconstants are shown in Table 10.

                                      TABLE 10                                    __________________________________________________________________________    Compd.    Yield % Elementary Analysis                                                                         IR(cm.sup.-1)                                 IV  R.sub.2                                                                             mp. (°C.)                                                                      (%)           NMR                                           __________________________________________________________________________    2   o-fluoro-                                                                           75%     C.sub.13 H.sub.7 O.sub.3 Cl.sub.2 F                                                         IRνmax(Nujol) 3400, 3170, 1665, 1655,                                      1610 cm.sup.-1                                phenyl    164˜165° C.                                                                C  H  Cl F  NMR(CDCl.sub.3) 9.50˜8.40(2H,br),                                       7.78˜7.10(4H,m), 7.03(1H,s)                               C;                                                                              51.86                                                                            2.34                                                                             23.55                                                                             6.31                                                              F;                                                                              51.88                                                                            2.47                                                                             23.49                                                                             6.28                                            3   2-thienyl                                                                           80%     C.sub.11 H.sub.6 O.sub.3 Cl.sub.2 S                                                         IRνmax(Nujol) 3360, 1720, 1710                                             cm.sup.-1                                               202˜204° C.                                                                C  H  Cl F  NMR(d.sub.6 -acetone) 8.97(2H,br),                                            7.97(1H, dd, J = 5.1), 7.53(1H,                                 C;                                                                              45.69                                                                            2.09                                                                             24.53                                                                            11.09                                                                            dd, J = 5.1), 7.17(1H, t, J = 5),                                             6.97(1H,s)                                                      F;                                                                              45.48                                                                            2.38                                                                             24.60                                                                            11.09                                            __________________________________________________________________________

EXAMPLE 6 Process 2: Method B (Step 1): ##STR21##

To a solution of 3.01 g (0.01 mol) of the starting material (IV-2)dissolved in 50 ml of DMF are added 480 g (0.02 mol) of sodium hydrideand then 1.88 g (0.011 mol) of benzyl bromide, and the mixture isstirred for 15 minutes at room temperature. The reaction mixture ispoured into ice-water, acidified by addition of diluted hydrochloricacid, and extracted with ethyl ether three times. The organic layer iswashed twice with water, dried over sodium sulfate, and evaporated todryness to give a residue, which is chromatographed on silica gel withdichloromethane as an eluent. After removal of the solvent, the productis recrystallized from benzene to give 2.791 g (yield 71.4) of thecaptioned compound (V-b-2), m.p. 156°-157° C.

In the same manner as above, the compounds (V-b-1) and (V-b-3) listed inthe following table are prepared, whose physical constants are shown inTable 11. ##STR22##

                                      TABLE 11                                    __________________________________________________________________________    Compd.      Yield % Elementary Analysis                                                                         IR(cm.sup.-1)                               V -b  R.sub.2                                                                             mp. (°C.)                                                                      (%)           NMR                                         __________________________________________________________________________    1     phenyl                                                                              77%     C.sub.20 H.sub.14 O.sub.2 Cl.sub.2                                                          IRνmax(Nujol) 3455, 1668, 1598, 1573                                       cm.sup.-1                                               171˜173° C.                                                                C  H  Cl    NMR(CDCl.sub.3) 6.97(1H,s), 7.40(5H,s),                                       7.90˜7.40(5H,m)                                           C;                                                                              64.36                                                                            3.78                                                                             19.00                                                                 F;                                                                              64.31                                                                            3.77                                                                             19.05                                             2     o-fluoro-                                                                           71%     C.sub.20 H.sub.13 O.sub.3 Cl.sub.2 F                                                        IRνmax(Nujol) 3200, 1655, 1615                                             cm.sup.-1                                   phenyl      156˜157° C.                                                                C  H  Cl F  NMR(CDCl.sub.3) 7.78˜6.98(4H,m),                                        ca. 7.41(5H), 7.07(1H,s),                                       C;                                                                              61.40                                                                            3.35                                                                             18.12                                                                            4.86                                                                             6.34(1H,s), 5.12(2H,s)                                          F;                                                                              61.41                                                                            3.40                                                                             18.24                                                                            4.73                                           3     2-thienyl                                                                           70%     C.sub.18 H.sub.12 O.sub.3 Cl.sub.2 S                                                        IRνmax(Nujol) 3450, 1648, 1600                                             cm.sup.-1                                               146˜148°C.                                                                 C  H  Cl F  NMR(CDCl.sub.3)7.73(1H, dd, J =  5,1),                                        7.32(1H, dd, J = 5,1), 7.08                                     C;                                                                              57.00                                                                            3.19                                                                             18.70                                                                            8.45                                                                             (1H, t, J = 5), 7.38(5H,s), 6.95(1H,s),                                       6.40(1H,b), 5.13(2H,s)                                          F;                                                                              56.87                                                                            3.30                                                                             18.56                                                                            8.44                                           __________________________________________________________________________

EXAMPLE 7 Process 2: Method A (Step 1) ##STR23##

To a solution of 3.217 mg of the starting material (IV-2) in 90 ml ofDMF is added a solution of sodium hydride (1.1 mol) and benzyl bromide(1.919 g, 1.05 mol) in DMF (10 ml), and the mixture is stirred at 100°C. for 2 hours, poured into ice-water, and acidified by addition ofhydrochloric acid. The mixture is extracted with ethyl ether and theorganic layer is washed with water and evaporated to dryness to give4.124 g of a residue, which is then chromatographed on silica gel (SiO₂,100 g) with dichloromethane as an eluent to give the compound (V'-a, 2)as the first fraction and the compound (V-a, 2) as the second fraction.The products are recrystallized from hexane to give 766 mg (yield 14.4%)of the compound (V'-a, 2), m.p. 84°-85° C. and 2.189 g (yield 52%) ofthe compound (V-a, 2), m.p. 109° -110° C., respectively.

In the same manner as above, the compounds (V-a, 1)(R² =o-phenyl) and(V-a, 3)(R² =2-thienyl) are prepared, whose physical constants are shownin Table 12.

                                      TABLE 12                                    __________________________________________________________________________               Yield %                                                                              Elementary Analysis                                                                           IR (cm.sup.-1)                              Compd.                                                                             R.sub.2                                                                             mp. (°C.)                                                                     (%)             NMR                                         __________________________________________________________________________    V-a-1                                                                              phenyl                                                                              34%    C.sub.26 H.sub.14 O.sub.3 Cl.sub.2 (Mw 373,                                                   IRνmax(Nujol) 3350,1665,1655,1597,158                                      0                                                      111˜112° C.                                                             C     H  Cl     NMR(CDCl.sub.3) 6.87(1H,s),7.45(5H,s),7.                                      93˜7.45(5H,m),5.73                                      C; 64.36                                                                            3.78                                                                             19.00  (1H,OH)                                                       F; 64.34                                                                            4.00                                                                             18.79                                              V-a-2                                                                              o-fluoro-                                                                           52%    C.sub.20 H.sub.13 O.sub.3 Cl.sub.2 S                                                          IRνmax(Nujol) 3210,1670,1610             phenyl     109˜110° C.                                                             C     H  Cl  F  NMR(CDCl.sub.3) 7.86˜7.00(4H,m),ca                                      .7.45(5H),6.93(1H,s),5.64                                     C; 61.40                                                                            3.35                                                                             18.12                                                                             4.86                                                                             (1H,s),5.14(2H,s)                                             F; 61.41                                                                            3.50                                                                             18.34                                                                             4.81                                           V'a-2                                                                              o-fluoro-                                                                           14.4%  C.sub.27 H.sub.19 O.sub.3 Cl.sub.2 S                                                          IRνmax(Nujol) 1645,1605NMR(CDCl.sub.3                                      ) 7.83˜6.99(4H,m),ca.                 phenyl     84˜85° C.                                                               C     H  Cl  F  7.39(10H),7.04(1H,s),5.13(2H,s),5.10(2H,                                      s)                                                            C; 67.37                                                                            3.98                                                                             14.73                                                                             3.95                                                             F; 67.28                                                                            3.95                                                                             14.61                                                                             3.90                                           V-a-3                                                                              2-thienyl                                                                           39%    C.sub.18 H.sub.12 O.sub.3 Cl.sub.2 S(Mw 379,                                                  IRνmax(Nujol) 3300,1640,1581                        159˜160° C.                                                             C     H  Cl  F  NMR(CDCl.sub.3) 7.78(H,dd,J                                                   = 5,1),7.42(1H,dd,J = 5,1),7.18                               C; 57.00                                                                            3.19                                                                             18.70                                                                             8.45                                                                             (1H,t,J = 5),7.43(5H,s),6.93(1H,s),5.68(                                      1H,s),5.15(2H,s)                                              F; 56.74                                                                            3.26                                                                             18.71                                                                             8.46                                           __________________________________________________________________________

EXAMPLE 8 Process 2': Method B (Step 2) ##STR24##

To a solution of 290 mg of 50% sodium hydride (washed out with petroleumether) in DMF (40 ml) are added a solution of 1.570 g (4.13 mmol) of thecompound (V-b, 3) (R² =2-thienyl) dissolved in DMF (40 ml) and then asolution of 822 mg (6 mmol) of α-epibromohydrin in DMF (5 ml). Themixture is stirred under heating at a temperature of 75° to 80° C. for 5hours. The reaction mixture is poured into ice-water and extracted withethyl ether, and the organic layer is washed with water, dried oversodium sulfate, and evaporated to leave 1.570 g of a neutral fractionand 280 mg of an acidic fraction.

A mixture of 1.570 g of the neutral fraction with 100 ml of hydrochloricacid is refluxed for 10 hours and extracted with dichloromethane. Theorganic layer is washed with water and evaporated to dryness to give1.500 g of a residue.

A mixture of the residue (1.500 g) with sodium hydroxide (500 mg) andethanol (30 ml) is refluxed for 15 minutes and extracted withdichloromethane. The organic layer is washed with water and evaporatedto give 1.350 g of a residual product, which is chromatographed onsilica gel (8 g of silica gel, dichloroethane:ethyl ether=4:1) and thenrecrystallized from ethyl ether/petroleum ether to give 830 mg (yield58%) of the captioned compound (Ia-b, 7), m.p. 137°-139° C. The physicalconstants of thus obtained compound was identical with those of thecompound (Ia-b, 7) prepared in Example 2.

In the same manner as above, the objective compounds (Ia-b, 8) (R²=phenyl), m.p. 201°-204° C. (yield 49%) and (Ia-b, 9) (R²=o-fluorophenyl), m.p. 197°-199° C. (yield 59%) were prepared via theintermediates (VI-b, 1) and (VI-b, 2) shown in Table 13.

                                      TABLE 13                                    __________________________________________________________________________                  Yield %                                                                              Elementary Analysis                                                                         IR (cm.sup.-1)                             Compd.                                                                              R.sub.2 mp. (°C.)                                                                     (%)           NMR                                        __________________________________________________________________________    VI-b-2                                                                               ##STR25##                                                                             -- 81˜82° C.                                                           C.sub.23 H.sub.17 O.sub.4 Cl.sub.2 F CHClF C: 61.76                           3.83 15.85 4.25 F: 61.64 4.01 15.79 4.15                                                    IR.sub.ν max(CHCl.sub.3) 1665, 1607                                        MR(CDCl.sub.3) 7.83˜7.07(4H,m),                                         ca. 7.38(5H), 7.03(1H,s), 5.09(2H,s),                                         4.38˜4.03(2H,m),                                                        3.45˜3.27(1H,m),                                                        2.86˜2.59                            VII-b-1                                                                              ##STR26##                                                                             -- 83˜84° C.                                                           C.sub.23 H.sub.18 O.sub.4 Cl.sub.2 CHCl C: 64.35                              4.23 16.52 F: 64.14 4.34 16.53                                                              IR.sub.ν max(Nujol) 1660, 1600,                                            1980 NMR(d.sub.6 -acetone) 7.23(1H,s),                                        7.90˜7.33(10,m), 5.27(2H,s),                                            4.55˜3.92(2H,m),                                                        3.47˜3.17(1H,m),                                                        2.83˜2.50(2H,m)                      __________________________________________________________________________

EXAMPLE 9 Process 2': Method A (Step 2) ##STR27##

A solution of 2.300 mg (6.05 mmol) of the compound (Va, 3) (R²=2-thienyl) in 40 ml of DMF is added to a solution of 350 mg (7.26 mmol;washed out with petroleum ether) of 50% sodium hydride in 40 ml of DMFand the mixture is heated at 70°-80° C. for 5 hours. After cooled, thereaction mixture is poured into ice-water and extracted with ethylether. The organic layer is washed with water and evaporated to drynessto give 2.700 g of a residue as a neutral fraction.

A mixture of 2.700 g of the neutral fraction and 140 ml of hydrochloricacid is refluxed for 5 hours and extracted with ethyl acetate. Theorganic layer is washed with a saturated aqueous solution of sodiumchloride and evaporated to give 2.300 g of a crystalline residue (VII-a,3), m.p. 187°-189° C.

A mixture of 2.300 g of the residue with sodium hydride (700 mg) andethanol (40 ml) is refluxed for 20 minutes and extracted withdichloromethane. The organic layer is washed with water and evaporatedto dryness to give 1.900 g of a residue, which is chromatographed onsilica gel. The benzene/dichloromethane fraction is recrystallized fromethyl acetate to give 1.317 g (yield 63%) of the compound (Ia-a, 6),m.p. 113°-114° C.

The physical constants of this product were identical with those of thecompound prepared in Example 1.

In the same manner as above, the compound (Ia-a 28) (R²=o-fluorophenyl), m.p. 109°-110° C. (yield 45%) is prepared, whosephysical constants were identical with those of the compound (Ia-a 28)prepared in Example 1.

Physical constants of the intermediates are shown in Table 14.

                                      TABLE 14                                    __________________________________________________________________________                Yield %                                                                              Elementary Analysis                                                                         IR (cm.sup.-1)                               Compd.                                                                             R.sub.2                                                                              mp. (°C.)                                                                     (%)           NMR                                          __________________________________________________________________________    VI-a-2                                                                              ##STR28##                                                                             -- oil                                                                             --            IR.sub.ν max(CHCl.sub.3) 1665, 1610                                        NMR(CDCl.sub.3) 7.84˜7.08(9H,m),                                        6.99(1H,s), 5.26(2H,s), 4.38˜3.85(2                                     H,m), ca. 3.35(1H), 2.93˜2.67(2H,m)    VII-a-2                                                                            "        --   C.sub.16 H.sub.12 O.sub.4 Cl.sub.3 F(Mw 393,                                                IR.sub.ν max(Nujol) 3470, 3230, 1630,                                      1603                                                     144˜146° C.                                                               C  H  Cl F  NMR(d.sub.6 -acetone) 7.81˜7.11(4H,                                     m), 7.23(1H,s), 7.5˜6.2(2H,                               C:                                                                              48.82                                                                            3.07                                                                             27.02                                                                            4.83                                                                             br), 4.33˜4.14(1H,m), ca.                                               4.24(2H), ca. 3.81(2H)                                          F:                                                                              48.46                                                                            3.16                                                                             26.80                                                                            4.86                                            __________________________________________________________________________

EXAMPLE 10 ##STR29##

To a solution of 2.00 g of the starting material (IIIa) dissolved in 50ml of acetone is dropwise added 5 ml of Jones' reagent (8N-CrO₃ /H₂ SO₄)over about 2 hours and methanol is then added thereto to kill the excessamount of chromic acid. After removal of the precipitate by filtration,the filtrate is evaporated under reduced pressure and extracted twicewith ether. The organic layer is washed twice with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, and evaporatedto give 1.94 g of a residue, which is then recrystallized fromdichloromethane/n-hexane to give 1.104 g (yield 52.1%) of7,8-dichloro-1,4-benzodioxane-2-carboxylic acid (VIII-1), m.p. 144°-148°C.

A mixture of 8.294 g of the compound (VIII-1) with dry ethanol (200 ml)and concentrated sulfuric acid (0.5 ml) is stirred for 5 hours under ananhydrous condition and extracted with dichloromethane 3 times. Theorganic layer is washed with water, a saturated sodium hydrogencarbonatesolution, and two portions of water, dried over sodium sulfate, andevaporated to give 9.051 g of a residue, which is recrystallized fromdichloromethane/petroleum ether to give 8.75 g (yield 94.8%) of ethyl7,8-dichloro-1,4-benzodioxane-2-carboxylate (VIII-2), m.p. 92°-94° C.

In the same manner as above, the following compounds were prepared,whose physical constants are shown in Table 15.

                                      TABLE 15                                    __________________________________________________________________________             Substituent                                                          Compd.   and its                                                                             m.p. Elementary Analysis                                                                         IR (cm.sup.-1)                              VIII S.M.*                                                                             position                                                                            °C.                                                                         (%)           NMR                                         __________________________________________________________________________    1    IIIa                                                                              --COOH                                                                              159˜161                                                                      C.sub.9 H.sub.6 Cl.sub.2 O.sub.4 (Mw 249,                                                   IRνmax(Nujol) 3040,1747,1600,1580                 (2)        C    H  Cl    NMR(d.sub.6 -acetone)                                                         7.88(1H,b),7.02,6.80(each 1H,d,J =                                            9),5.20                                                         C; 43.40                                                                           2.43                                                                             28.47 (1H,t,J = 3),4.70˜4.23(2H,m)                              F; 43.20                                                                           2.55                                                                             28.57                                             2    IIIa                                                                              --COOEt                                                                             85˜88                                                                        C.sub.11 H.sub.19 O.sub.4 Cl.sub.2 (Mw, 277,                                                IRνmax(Nujol) 1742,1600,1580                      (2)        C    H  Cl F  NMR(CDCl.sub.3) 7.00,6.72( 1H,d,J =                                           8),4.98(1H,t,J = 8),4.67˜                                 C; 47.68                                                                           3.64                                                                             25.59 4.17(2H,m),4.27(2H,q,J = 8),1.27(3H,t,J                                       = 8)                                                            F; 47.54                                                                           3.72                                                                             25.71                                             3    IIIb                                                                              --COOH                                                                              186˜188                                                                      C.sub.9 H.sub.6 O.sub.4 Cl.sub.2 (Mw 249,                                                   IRνmax(Nujol) 3600˜2200(br),173                                      0                                                    (3)        C    H  Cl    NMR(d.sub.6 -acetone) 7.06,6.90(2                                             × 1H,d,J =  9),5.08(1H,t,J =                              C; 43.40                                                                           2.43                                                                             28.47 3),4.66,4.42(2 × 1H,dd,J =                                              3.13),9.5˜8.0(1H,br)                                      F; 43.89                                                                           2.86                                                                             27.36                                             4    IIIb                                                                              --COOEt                                                                             82˜83                                                                        C.sub.11 H.sub.10 O.sub.4 Cl.sub.2 (Mw 277,                                                 IRνmax(Nujol) 1770,1750,1583NMR(CDCl.                                      sub.3) 7.03,6.86(2 × 1H                        (3)        C    H  Cl    d,J = 9),4.82(1H,d,J = 4),ca.4.47(2H),4.                                      26(2H,q,J = 7),1.26                                             C; 47.68                                                                           3.64                                                                             25.59 (3H,t,J = 7)                                                    F; 47.46                                                                           3.64                                                                             25.49                                             __________________________________________________________________________     Note                                                                          *starting material                                                       

EXAMPLE 11 ##STR30##

A mixture of 2.00 g of the compound (VIII-2) obtained in Example 10 withα,α-dichloromethyl methyl ether (12 ml) and dichloromethane (40 ml) iscooled on an ice-bath and 4.284 g of aluminium chloride is added theretoover about 20 minutes. The reaction mixture is stirred at roomtemperature for 3 hours. After confirming completion of the reaction byTLC, the reaction mixture is poured into ice-water/concentratedhydrochloric acid and extracted with dichloromethane 3 times. Theorganic layer is washed twice with a saturated aqueous solution ofsodium chloride, dried over sodium sulfate, and evaporated to give 2.242g of a residue.

This is passed through Lober column B (made by Merck) withbenzene/acetone (30/1) as an eluent. The product in the earliestfraction is recrystallized from acetone/ether/petroleum ether to give1.031 g (yield 47%) of the objective ethyl6-formyl-7,8-dichloro-1,4-benzodioxane-2-carboxylate (Ib'-51), m.p.101°-102° C. And the product in the later fractions are alsorecrystallized in the same manner as above to give 1.057 g (yield 49%)of ethyl 5-formyl-7,8-dichloro-1,4-benzodioxane-2-carboxylate (Ib'-50),m.p. 110°-113° C.

Titanium tetrachloride was employed in place of aluminium chloride, andthe reaction was carried out in the same manner as above to give thecompounds (Ib'-50) in 19% yield and (Ib'-51) in 39% yield.

In the same manner as above, the following compounds were prepared,whose physical constants are shown in Table 16.

                                      TABLE 16                                    __________________________________________________________________________     ##STR31##                                                                    Compd.                                                                             position                                                                 Ia-a of         m.p. Elementary Analysis                                                                        IR (cm.sup.-1)                              or Ib'                                                                             formyl                                                                             R'    °C.                                                                         (%)          NMR                                         __________________________________________________________________________    Ia-a-39                                                                            5    CH.sub.2 OAc                                                                        142˜144                                                                      C.sub.12 H.sub.19 O.sub.6 Cl.sub.2 (Mw305,                                                 IRνmax(Nujol) 1758,1678,1580                                  C    H   Cl  NMR(d.sub.6 -acetone)                                                         10.25(1H,s),7.40(1H,s),                                          C; 47.24                                                                           3.30                                                                              23.24                                                                             4.73˜4.17(5H,m),2.07(3H,s)                                 F; 47.06                                                                           3.26                                                                              22.99                                           Ia-a-40                                                                            6    CH.sub.2 OAc                                                                        90˜92                                                                        C.sub.12 H.sub.19 O.sub.6 Cl.sub.2 (Mw305,                                                 IRνmax(Nujol) 1732,1578,1590,1558                             C    H   Cl  NMR(d.sub.6 -acetone)                                                         10.23(1H,s),7.33(1H,s),                                          C; 47.24                                                                           3.30                                                                              23.24                                                                             4.73˜4.07(3H,m),2.07(3H,s)                                 F; 47.25                                                                           3.23                                                                              23.30                                           Ia-a-41                                                                            5    CH.sub.2 OH                                                                          99˜100                                                                      C.sub.10 H.sub.8 O.sub.4 Cl.sub.2 (Mw263,                                                  IRνmax(Nujol) 3440,1680,1585                                  C     H  Cl  NMR(d.sub.6 -acetone)                                                         10.30(1H,s),7.40(1H,s),                                          C; 45.66                                                                           3.07                                                                              26.95                                                                             4.77˜4.25(3H,m),4.07˜3.87(2H                                      ,broad)                                                          F; 45.58                                                                           3.19                                                                              26.67                                           Ia-a-42                                                                            6    CH.sub.2 OH                                                                         127-128                                                                            C.sub.10 H.sub.8 O.sub.4 Cl.sub.2 (Mw263,                                                  IRνmax(Nujol) 3450,1690˜1670,15                                      91,1560                                                          C    H   Cl  NMR(d.sub.6 -acetone)                                                         10.30(1H,s),7.33(1H,s),                                          C; 45.66                                                                           3.07                                                                              26.95                                                                             4.70˜4.17(3H,m),4.07˜3.83(2H                                      ,b)                                                              F; 45.40                                                                           3.20                                                                              26.89                                           Ib'-50                                                                             5    COOEt 110˜113                                                                      C.sub.12 H.sub.10 O.sub.6 Cl.sub.2 (Mw305,                                                 IRνmax(Nujol) 3080,1755,1690,1588,157                                      5                                                                C    H   Cl  NMR(d.sub.6 -acetone)                                                         10.20(1H,s),7.40(1H,s),                                          C; 47.24                                                                           3.30                                                                              23.24                                                                             5.37(1H,t,J = 2),4.73˜4.40(2H,m),4                                      .27(2H,                                                          F; 47.11                                                                           3.41                                                                              22.90                                                                             q,J = 8),1.25(3H,t,J = 8)                   Ib'-51                                                                             6    COOEt 101˜102                                                                      C.sub.12 H.sub.10 O.sub.6 Cl.sub.2 (Mw305,                                                 IRνmax(Nujol) 3070,3040,1757,1690,159                                      7,                                                               C    H   Cl  1560                                                             C; 47.24                                                                           3.30                                                                              23.24                                                                             NMR(d.sub.6 -acetone)                                                         10.33(1H,s),7.33(1H,s),                                          F; 47.07                                                                           3.31                                                                              22.91                                                                             5.40(1H,t,J = 2),4.70˜4.30(2H,m),4                                      .25(2H,                                                                       q,J = 8),1.25(3H,t,J = 8)                   Ib'-52                                                                             5    COOH  254˜257                                                                      C.sub.10 H.sub.6 O.sub.6 Cl.sub.2 (Mw277,                                                  IRνmax(Nujol) 1718,1683,1583                                  C    H   Cl  NMR(d.sub.6 -acetone)                                                         9.27(1H,s),7.42(1H,s),                                           C; 43.35                                                                           2.18                                                                              25.59                                                                             6.43(1H,b),5.36(1H,t,J                                                        = 3),4.90˜4.47(2H,m)                                       F; 43.29                                                                           2.58                                                                              25.20                                           Ib-20                                                                              6    COOH  262˜263                                                                      C.sub.10 H.sub.5 O.sub.6 Cl.sub.2 (Mw277,                                                  IRνmax(Nujol) 1755,1658,1593,1558                             C    H   Cl  NMR(d.sub.6 -acetone)                                                         10.33(1H,s),7.35(1H,s),                                          C; 43.35                                                                           2.18                                                                              25.59                                                                             5.40(1H,t,J = 3),4.75˜4.33(2H,m)                           F; 43.07                                                                           2.36                                                                              25.53                                           __________________________________________________________________________

EXAMPLE 12 ##STR32##

A solution of 1194 mg of the compound (Ib'-3), 449 mg (4 equiv.) ofparaformaldehyde, and 710 mg of p-toluenesulfonic acid monohydratedissolved in 15 ml of dioxane is stirred at 90° C. on an oil-bath for 27hours. After completion of the reaction, the reaction mixture isconcentrated and combined with benzene. The acidic portion of themixture is moved into a saturated sodium hydrogencarbonate solution,made acidic with hydrochloric acid, and extracted with benzene 3 times.The organic layer is washed twice with water, dried over sodium sulfate,and evaporated to give 1474 mg of a residue, which is thenchromatographed on 30 g of silica gel to give 748 mg of a product as thefraction of methylene chloride/ether (9/1). This is recrystallized fromisopropyl ether/hexane to give 424 mg (m.p. 142°-143° C.) and 141 mg(m.p. 141°-143° C.) of the objective2-carboxyl-5-(2-ethylacryloyl)-7,8-dichloro-1,4-benzodioxane (Ib'-57),total amount 565 mg, total yield 45.6%.

Anal. Calcd. (%) for C₁₄ H₁₂ O₅ Cl₂ (molecular weight 331.15): C; 50.78,H; 3.65, Cl; 21.41. Found (%): C; 50.60, H; 3.82, Cl; 21.33.

IR(Nujol) νmax (cm⁻¹): 3500-2800(b), 1765, 1630.

NMR(d₆ -acetone) δppm: 7.9-6.9(1H, b), 6.97(1H, s), about 5.91,5.64(2×1H, s), 5.25(1H, t, J=3 Hz), 4.59, 4.37(2H×1H, d, d, J=3.13),2.37(2H, q, J=7 Hz), 1.06(3H, t, J=7 Hz).

General Procedure ##STR33##

A solution of a starting material, paraformaldehyde, andp-toluenesulfonic acid dissolved in dioxane is refluxed for about 24hours, and the resulting mixture is treated in a conventional manner togive an objective compound (Ib').

The starting material and physical constants on each compound obtainedare shown in Table 17.

                                      TABLE 17                                    __________________________________________________________________________    Compd.                                                                             S.M.                                                                             Position                                                                            Position                                                                              m.p. Elementary Analysis                                                                        IR (cm.sup.-1)                        Ib'  Ib'                                                                              of --CO.sub.2 H                                                                     of acyl                                                                            R.sub.6                                                                          °C.                                                                         (%)          NMR (δ, Hz)                     __________________________________________________________________________    58    1 2     5    Me 160˜162                                                                      C.sub.13 H.sub.10 O.sub.6 Cl.sub.2 (Mw 317,                                   128)         IRνmax(Nujol)                                                              3500˜2300(br),1765,                                        C    H   Cl  1635,1622                                                        C; 49.24                                                                           3.18                                                                              22.36                                                                             NMR(d.sub.6 -acetone)                                                         9.4˜8.3(1H,br),                                            F; 49.39                                                                           3.36                                                                              22.06                                                                             6.98(1H,s),ca.5.98(1H),5.64(1H,s),                                            N                                                                             5.26(1H,t,J = 3),4.59,4.35(2                                                  × 1H,dd,                                                                J = 3,12)1.92(3H,d,J = 1.5)           59   22 2     6    Me 155˜158                                                                      C.sub.13 H.sub.10 Cl.sub.2 O.sub.5 (Mw 317,                                   128)         IRνmax(Nujol)                                                              3200,1650,1600,1570                                              C    H   Cl  NMR(CDCl.sub.3)                                                               8.53(1H,s),6.76(1H,s),                                           C; 49.24                                                                           3.18                                                                              23.38                                                                             5.99,5.54(2 × 1H,s),5.03(1H,                                            t,J = 3),                                                        F; 49.35                                                                           3.46                                                                              21.82                                                                             4.63˜4.22(2H,m),2.02(3H,s)      60   23 2     6    Et 134˜135                                                                      C.sub.14 H.sub.12 O.sub.6 Cl.sub.2 (Mw 331,                                   155)         IRνmax(Nujol)                                                              3500˜2800(br),1760,                                        C    H   Cl  1650                                                             C; 50.78                                                                           3.65                                                                              21.41                                                                             NMR(d.sub.6 -acetone)                                                         8.0˜6.3(1H,b),                                             F; 50.65                                                                           3.56                                                                              21.15                                                                             6.83(1H,s),ca.600,5.60(2 ×                                              1H),5.27                                                                      (1H,t,J = 3),2.66,4.42(2 ×                                              1H,dd,J =                                                                     3.13),2.42(2H,q,J                                                             = 7),1.11(3H,t,J =                                                            7)                                    61   36 3     6    Et 187˜189                                                                      C.sub.14 H.sub.12 O.sub.6 Cl.sub.2 (Mw 331,                                   155)         IRνmax(Nujol)                                                              3600˜2200(br),1710,                                        C    H   Cl  1650                                                             C; 50.78                                                                           3.65                                                                              21.41                                                                             NMR(d.sub.6 -acetone)                                                         7.6˜6.9(1H,br),                                            F; 50.66                                                                           3.60                                                                              21.49                                                                             6.93(1H,s),6.01(1H,t,J                                                        = 1.5),5.63                                                                   (1H,s),5.16(1H,t,J                                                            =3),4.75,4.53(2 ×                                                       1H,dd,J = 3.13),2.43(2H,q,J =                                                 7),1.12                                                                       (3H,t,J = 7)                          __________________________________________________________________________

EXAMPLE 13 ##STR34##

To a solution of 1.03 g of2-acetoxymethyl-7,8-dichloro-1,4-benzodioxane-5-carbaldehyde (Ia-a-39)in 70 ml of acetone is added 2 ml of 8N-chromic acid/sulfric acid. Themixture is stirred at room temperature for about 2.5 hours and thenfiltered after the confirmation by TLC that no starting material isremained. The filtrate is concentrated under reduced pressure to give aresidue, which is extracted with dichloromethane. The organic layer iswashed with water and evaporated to give 1.004 g (93%) of2-acetoxymethyl-7,8-dichloro-1,4-benzodioxane-5-carboxylic acid(Ia-a-43: R³ '=Ac), which is recrystallized from dichloromethane/etherto yield crystals, m.p. 144°-145° C.

Anal. Calcd. (%) for C₁₂ H₁₀ O₆ Cl₂ (molecular weight 321.112): C;44.89, H; 3.14, Cl; 22.08. Found (%): C; 44.62, H; 3.13, Cl; 21.67.

IR(Nujol) νmax (cm⁻¹): 2600, 1750, 1700, 1590, 1570.

NMR(CDCl₃) δppm: 7.68(1H, s), 4.87-4.17(5H, m), 2.10(3H, s).

To a solution of 1.00 g of the product (Ia-a-43) obtained abovedissolved in a mixture of THF (30 ml) with ethanol (10 ml) is added anaqueous potassium carbonate solution (a solution of 2 g of potassiumcarbonate dissolved in 20 ml of water) and the resulting mixture isheated at 70°-80° C. for 5 minutes, then allowed to stand at roomtemperature for an hour. The mixture is made acid by addition ofhydrochloric acid and extracted with dichloromethane. The organic layeris washed with water, dried, and evaporated to give 980 mg of a residue,which is recrystallized from dichloromethane/ether to give 836 mg of2-hydroxymethyl-7,8-dichloro-1,4-benzodioxane-5-carboxylic acid(Ia-a-44: R³ '=H), m.p. 175°-177° C.

Anal. Calcd. (%) for C₁₀ H₈ O₅ Cl₂ (molecular weight 279.075): C; 43.04,H; 2.89, Cl; 25.41. Found (%): C; 42.80, H; 2.83, Cl; 25.65.

IR(Nujol) νmax (cm⁻¹): 3200, 1698-1705, 1585, 1565.

NMR(d₆ -acetone) δppm: 7.58(1H, s), 4.70-4.20(3H, m), 3.93(2H, d,J=4.0).

According to the same reaction conditions as above, the followingcarboxylic acids were prepared from2-acetoxymethyl-7,8-dichloro-1,4-benzodioxane-6-carbaldehyde (Ia-a-40).

*2-Acetoxymethyl-7,8-dichloro-1,4-benzodioxane-6-carboxylic acid, m.p.178°-180° C. (from dichloromethane/ether).

Anal. Calcd. (%) for C₁₂ H₁₀ O₆ Cl₂ (molecular weight 321.12): C; 44.89,H; 3.14, Cl; 22.08. Found (%): C; 44.61, H; 3.24, Cl; 22.34.

IR(Nujol) νmax (cm⁻¹): 3100, 1728, 1700, 1598, 1561.

NMR (d₆ -acetone) δppm: 7.47(1H, s), 4.87-4.07(5H, m), 2.07(3H, s).

*2-Hydroxymethyl-7,8-dichloro-1,4-benzodioxane-6-carboxylic acid, m.p.220°-221° C. (from acetone/ether).

Anal. Calcd. (%) for C₁₀ H₈ O₅ Cl₂ (molecular weight 279.075): C; 43.04,H; 2.89, Cl; 25.41. Found (%): C; 42.77, H; 2.96, Cl; 25.43.

NMR(d₆ -acetone) δppm: 7.40(1H, s), 4.67-4.13(3H, m), 3.90(2H, d, J=4).

The compounds (I) of the present invention have excellentantihypertensive and diuretic actions and are very useful for thetreatment for hypertensives. They can be administered orally,intravenously, or hypodermically to human at a respective daily dosageof 0.1-2 mg/kg, 0.005-0.1 mg/kg, or 0.02-0.4 mg/kg. Diuretic effect andhyperuricosuric effect on the typical compounds are explained by thefollowing Experiments.

EXPERIMENT 1 Estimation of Diuretic Effects Test Method

a. Diuretic Effect on Rats

Slc:SD 8-week-old rats (male, about 250 g body-weight each) were usedfor the test. A few lumps of sugar in place of ordinary diets were givenon the morning of the day before the test day and 5% glucose solutionwas given orally at a rate of 20 ml/kg in the evening (approximately at4 p.m.) of the test day. In the morning for the test, a sample which wasprepared by suspending or dissolving a test compound in 2% gum arabicwas orally administered to each at a dose of 20 ml/kg. On the otherhand, mere by 2% gum arabic was orally administered to the control groupat 20 ml/kg. Immediately after the administration, the test animals wereput in a plastic cage for the metabolic tests and their urine sampleswere collected for 5 hours. The cumulative urine volume, urinary sodium,and urinary potassium were quantitatively determined.

b. Diuretic Effect on Mice

Slc:ddy 5-week-old mice (female, about 20 g body-weight each) were usedfor the test. From the morning of the day before the test day, the micewere fasted but water. In the morning of the test day, a sample whichwas prepared by suspending or dissolving a test compound in 2% gumarabic was orally administered to each at 30 ml/kg. On the other hand,mere by 2% gum arabic was orally administered to the control group at 30ml/kg. Immediately after the administration, 5 mice employed were put ina plastic cage for the metabolic tests and their urine samples werecollected for 4 hours. The cumulative urine volume, urinary sodium, andurinary potassium were quantitatively determined.

Results

Test results are shown in the following Table 1. Indacrinone (MerckSharp & Dohme) was used as a referrence.

                                      TABLE 1                                     __________________________________________________________________________           Experiment 1-a on Rats                                                                             Experiment 1-b on Mice                                   Dose                                                                              Urine Vol.*                                                                          Na.sup.+ *                                                                         K.sup.+ *                                                                          Dose                                                                              Urine Vol.*                                                                          Na.sup.+ *                                                                         K.sup.+ *                         Compound                                                                             mg/kg                                                                             ml/kg  mEg/kg                                                                             mEg/kg                                                                             mg/kg                                                                             ml/kg  mEg/kg                                                                             mEg/kg                            __________________________________________________________________________    Ib'3   50  39.0/29.6                                                                            2.21/0.76                                                                          0.68/0.22                                                                          30  54.0/30.3                                                                            4.31/0.64                                                                          1.40/0.53                         (Example 3)                                                                   Ib'1   50  50.8/32.6                                                                            3.04/0.71                                                                          0.86/0.25                                                                          30  54.5/25.9                                                                            5.68/0.78                                                                          1.41/0.55                         (Example 3)                                                                   Ib'8   50  32.8/24.1                                                                            1.36/0.46                                                                          0.48/0.27                                                                          30  52.8/26.3                                                                            4.56/0.93                                                                          1.51/0.77                         (Example 3)                                                                   Ib'4   50  38.8/23.5                                                                            3.54/0.75                                                                          1.42/0.42                                                                          30  60.2/24.7                                                                            5.78/0.82                                                                          1.68/0.57                         (Example 3)                                                                   Ib'6   50  48.8/24.7                                                                            3.90/0.59                                                                          1.27/0.39                                                                          30  46.4/24.7                                                                            3.02/0.82                                                                          1.14/0.57                         (Example 3)                                                                   Ib'41  50  30.1/28.3                                                                            1.49/0.54                                                                          0.58/0.25                                                                          30  29.0/22.1                                                                            1.08/0.58                                                                          0.88/0.57                         (Example 3)                                                                   Ia-a1  50  36.6/32.6                                                                            1.62/0.71                                                                          0.47/0.25                                                                          30  33.7/25.9                                                                            2.39/0.78                                                                          0.86/0.55                         (Example 1)                                                                   Ia-a3  50  40.0/32.6                                                                            1.93/0.71                                                                          0.48/0.25                                                                          30  23.2/22.1                                                                            1.09/0.58                                                                          0.68/0.57                         (Example 1)                                                                   Referrence                                                                           50  34.3/29.4                                                                            1.26/0.55                                                                          0.50/0.25                                                                          30  71.9/29.2                                                                            6.44/0.77                                                                          1.87/0.67                         __________________________________________________________________________     *Test Group/Control Group                                                

EXPERIMENT 2 Estimation of Hyperuricosuric Effects Test Method

a. Experiment for Clearance

Slc:Wister 10-week-old male rats were used for the test. Potassiumoxonate was intraperitoneally (hereinafter abbreviated as i.p.)administered to the test animals at a dose of 250 mg/kg in order tomeasure uric acid clearance and inulin clearance. Ninety minutes later,canulae were placed into the femoral artery, femoral vein, and urinarybladder and a tube for administration of drugs was placed into abdominalcavity on each animal under anesthesia with 50 mg/kg i.p. ofpentobarbital.

Exact 2 hours after the first administration, potassium oxonate wasadministered again i.p. at a dose of 250 mg/kg and then 60% urethane (2ml/kg) and 15% inulin (4 ml/kg) were subcutaneously injected. A mixtureof 4% mannitol/1.5% inulin/0.9% saline was infused at a flow rate of 0.1ml/min to the animal on a plate kept at 30° C. After the equilibrium for40 minutes, arterial blood (0.2 ml each) samples were collected 6 timesevery 20 minutes, and five 20-minutes urines were collected. Immediatelyafter the collection of every blood sample, the serum was separatedtherefrom, and the serum samples and the urine samples were stored in arefrigerator. A test compound was suspended in 1% gum arabic and thesuspension was intraperitoneally administered at 2 ml/kg.

b. Measurement of Uric acid and Inulin

Uric acid in the serum or in the urine was quantitatively analyzed bythe method of Yonetani et al's. [Y. Yonetani et al., Japanese Journal ofPharmacology 30, 829-840 (1980)]. Substantially by the fluorescencemethod of Vurek's and Pegram's using dimedone reagent [Vurek, G. G.,Pegram, S. E., Anal. Biochem. 16, 409-419 (1966)], inulin was alsoquantitatively analyzed in the following manner. To 0.1 ml of diluteddeprotenized-serum or urine employed for the measurement of uric acidwas added 5 ml of 1% dimedone/phosphoric acid solution and the resultingmixture was heated for 5 minutes. The mixture was cooled in ice-coldwater, combined with 2.0 ml of acetic acid, then shaken well, and thefluorescence was measured at 410 nm in the excitation wave length at 360nm.

Test Results

In order to estimate hyperuricosuric effect on tienilic acid as areferrence, tienilic acid was administered to the animals at a dose of100 mg i.p. and urine volume (ml/kg min.), urinary uric acid (ml/kgmin.), and fractional excretion of uric acid [FEua (μg/ml): (Uric acidClearance)/(Inulin Clearance)] were measured. In the tables, "zero"minute means the time when a drug was administered. A fraction beforethe administration and 4 fractions after the administration wereemployed for the measurement.

Results are shown in the following Table 2. Experiments with 1% gumarabic solution (2 ml/kg i.p.) were also made.

                  TABLE 2                                                         ______________________________________                                                  Urine Volume Urinary ua.*.sup.1                                                                        FE ua                                      Time (minutes)                                                                          (ml/kg min.) (ml/kg min.)                                                                              (μ g/ml)                                ______________________________________                                        a. 1% gum arabic at 2 ml/kg i.p.                                              -20 to 0  0.32         0.166       0.650                                       0 to 20  0.30         0.182       0.660                                      20 to 40  0.29         0.191       0.654                                      40 to 60  0.29         0.159       0.566                                      60 to 80  0.27         0.170       0.581                                      Increase (%)*.sup.2                                                                     --           --          --                                         b. Tienilic acid at 100 mg/kg i.p.                                            -20 to 0  0.31         0.176       0.648                                       0 to 20  0.35         0.212       0.634                                      20 to 40  0.37         0.296       0.694                                      40 to 60  0.33         0.329       0.740                                      60 to 80  0.30         0.359       0.744                                      Increase (%)*.sup.2                                                                       9            70           8                                       ______________________________________                                         NOTE:                                                                         *.sup.1 "ua" means uric acid                                                  *.sup.2 Increase (%) = [(Mean value after administration) ÷ (value        before administration) - 1] ×100                                   

As indicated in the table, no significant increase in urine volume,urinary uric acid, and FE ua. was seen in the control group, whileslightly positive diuretic effect and increase in urinary uric acid andFE ua. were observed in the Thienilic acid (at 100 mg/kg i.p.) group asreferences. In addition, no remarkable pharmacological activitiesconcerning those test parameters were observed in the Thienilic acid (at50 mg/kg i.p.) group.

Experiments on the compounds of this invention were made in the samemanner as explained above and diuretic effect and hyperuricosuric effectwere estimated. Increase (%) concerning each parameter on the typicalcompounds was shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Test     Dose (mg) Increase (%)                                               Compound i.p.      Urine Vol. Urinary ua.                                                                           FE ua.                                  ______________________________________                                        Tienilic 50        --         --      --                                      acid     100        9         70       8                                      I b'3    50        59         45      23                                      I b'1    50        91         46       8                                      I b'8    50        --         37      17                                      I b'2    50        106        67      27                                      ______________________________________                                    

Conclusion

The compounds of the present invention are confirmed to be excellentdiuretic antihypertensives having uricosuric activities from thoseexperiments.

What we claim is:
 1. A compound of the formula: ##STR35## wherein R¹ isoptionally protected hydroxymethyl or carboxy; R² is hydrogen, straightor branched chain lower alkyl or lower alkenyl, C₄ -C₇ cycloalkyl,optionally substituted phenyl, phenyl(lower alkyl), hydroxy, thienyl, orfuryl; and the dotted line indicates the presence or absence of a doublebond.
 2. A process for production of the compounds of the formula:##STR36## wherein R¹ is optionally protected hydroxymethyl or carboxy;R² is hydrogen, straight or branched chain lower alkyl or lower alkenyl,C₄ -C₇ cycloalkyl, optionally substituted phenyl, phenyl(lower alkyl),hydroxy, thienyl, or furyl; and the dotted line indicates the presenceor absence of a double bond,which is characterized by reaction of3,4-dichloro-1,2-benzenediol of the formula: ##STR37## withα-epihalohydrin or the equivalent reagent thereof in the presence of abase followed by acylation in the presence of Lewis acid; orcharacterized by acylation of 3,4-dichloro-1,2-benzenediol in thepresence of Lewis acid followed by reaction with α-epihalohydrin or theequivalent reagent thereof in the presence of a base, and if necessary,subsequent oxidation or dehydrogenation after the oxidation.